Hydrogel-Driven Drug Dosage Form

ABSTRACT

A controlled release dosage form has a coated core with the core comprising a drug-containing composition and a water-swellable composition, each occupying separate regions within the core. The drug-containing composition comprises a low-solubility drug and a drug-entraining agent. The coating around the core is water-permeable, water-insoluble and has at least one delivery port therethrough. A variety of formulations having specific drug release profiles are disclosed.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to a dosage form that provides acontrolled release of a low-solubility beneficial agent, or drug, to anenvironment of use.

[0002] Osmotic and hydrogel-driven drug delivery devices for the releaseof a drug have been known in the art for some time. Exemplary dosageforms have included a tablet comprising a semipermeable wall surroundinga compartment containing the drug and a layer of swellable hydrogel,with the drug being delivered through a passageway in the semipermeablewall by swelling of the hydrogel, as described in U.S. Pat. No.4,327,725; another tablet comprising a wall permeable to an exteriorfluid but impermeable to the drug, the wall surrounding a compartmentcontaining two osmotic agents, two expandable polymers and the drug, asdescribed in U.S. Pat. No. 4,612,008; drug dispersed in a swellablehydrogel matrix core that releases the drug by diffusion into theenvironment of use, as described in U.S. Pat. No. 4,624,848; a hydrogelreservoir containing a multiplicity of tiny pills wherein each tiny pillconsists of a wall surrounding a drug core, as described in U.S. Pat.No. 4,851,232; and a two-layered tablet wherein one layer is drug mixedwith a hydrogel and the other layer is a hydrogel, as described in U.S.Pat. No. 5,516,527.

[0003] While the conventional dosage forms described above arefunctional, nonetheless such dosage forms suffer from a variety ofdrawbacks. A controlled release dosage form should ideally deliversubstantially all of the drug from the dosage form to the environment ofuse. However, a common problem encountered by osmotic andhydrogel-driven dosage forms, particularly when the drug has low aqueoussolubility, is that residual drug is left in the tablet interior afterthe hydrogel or other swellable material has completely swelled. Thisresidual drug is not available for absorption and, accordingly, suchdosage forms require increased amounts of drug to compensate for thefailure of the system to release all of the drug into the environment ofuse.

[0004] In addition, the controlled release dosage form must operatewithin certain size constraints, and yet be capable of delivering mostor all of the drug to the environment of use. Dosage forms, particularyfor humans, are limited in size, and are usually less than 1 gram, morepreferably less than 700 mg in weight. However, for some types of drugs,the dose amount may make up to half or even more of the weight of thedosage form. The water-swellable materials that provide the delivery ofthe drug must in instances where the dose is high be capable ofproviding a highly efficient delivery of the drug, since very little ofthe dosage form may be available for the swellable material or otherexcipients.

[0005] In addition, it is often desired that the dosage form beginextruding drug relatively quickly upon entering the use environment.However, many delivery systems exhibit a time lag before extruding drug.This is particularly a problem when the drug has low aqueous solubilityor is hydrophobic. Several techniques have been proposed to reduce thetime lag, but each has its own drawback. One technique has been toprovide high-permeabilitiy coatings by utilizing thin coatings aroundthe dosage form. While this technique provides a quicker uptake offluid, the thin coating lacks strength and often bursts in use orprovides insufficient protection to the dosage form which becomessusceptible to damage during handling. Yet another technique hasinvolved providing pores or one or more passageways that communicatewith the water-swellable materials, but this often leads to unacceptableamounts of residual drug. Another technique involves coating the dosageform with an immediate release drug formulation, but this requiresadditional processing steps and provides a dosage form with twodifferent release rates, which may be undesirable.

[0006] Yet another problem encountered with conventional osmotic andhydrogel-driven drug delivery systems is that such dosage forms oftenrequire the presence of osmagents. Osmagents are selected such that theygenerate an osmotic pressure gradient across the barrier of thesurrounding coating. The osmotic pressure gradient drives the permeationof water into the tablet and the resulting buildup of sufficienthydrostatic pressure, which forces the drug through the delivery port.These osmagents increase the weight of the dosage form, thus limitingthe amount of drug which may be contained in the dosage form. Inaddition, the presence of additional ingredients in the dosage form,such as osmagents, increases the costs of manufacture due to the need toinsure uniform concentrations of the ingredients throughout the dosageform, and may have other drawbacks such as adverse effects oncompression properties and on drug stability.

[0007] Accordingly, there is still a need in the art for a controlledrelease dosage form that results in a highly efficient delivery of drugto an environment of use with very little residual drug, that allowslarge drug loading so as to minimize the dosage size, that beginsreleasing drug soon after entering the environment of use, and thatlimits the number of necessary ingredients. These needs and others whichwill become apparent to one skilled in the art are met by the presentinvention, which is summarized and described in detail below.

BRIEF SUMMARY OF THE INVENTION

[0008] The various aspects of the invention each provide a controlledrelease drug dosage form having a core comprising a drug-containingcomposition and a water-swellable composition. The drug-containingcomposition and the water-swellable composition occupy separate regionswithin the core. The drug-containing composition comprises alow-solubility drug and a drug-entraining agent. A coating around thecore is water-permeable, water-insoluble and has at least one deliveryport therethrough.

[0009] In a first aspect of the invention, the drug-containingcomposition further includes a swelling agent having a swelling ratio ofat least 3.5, and the drug-entraining agent comprises at least 15 wt %of the drug-containing composition.

[0010] In a second aspect of the invention, the mass ratio of thedrug-containing composition to the water-swellable composition has avalue of at least 1.5, and the water-swellable composition comprises awater-swellable agent and a tableting aid, the water-swellablecomposition having a swelling ratio of at least 3.5, and a strength ofat least 3 Kp/cm² (where Kp is Kiloponds).

[0011] In a third aspect of the invention, the water-swellablecomposition comprises a swelling agent. The coating around the core hasa minimum durability of 1 Kp/cm², and a minimum water flux (40/75) of atleast 1.0×10⁻³ gm/cm²-hr.

[0012] In a fourth aspect of the invention, the coating is porous and isformed from a substantially homogeneous solution comprising a solvent, ahydrophilic cellulosic polymer, and a non-solvent.

[0013] In a fifth aspect of the invention, the drug-containingcomposition further comprises a fluidizing agent. Following introductioninto an environment of use, the dosage form releases at least about 70wt % of the low-solubility drug to the use environment within about 12hours.

[0014] In a sixth aspect of the invention, the drug-containingcomposition further comprises a solubilizer. When the drug is a basicdrug, the solubilizer may be an organic acid.

[0015] In a seventh aspect of the invention, the low-solubility drug isin the form of an amorphous dispersion.

[0016] In an eighth aspect of the invention, a method is provided fortreating a patient in need of a drug by administering a therapeuticallyeffective amount of the drug in a dosage form of the invention.

[0017] In one embodiment, the dosage form includes aconcentration-enhancing polymer.

[0018] The various aspects of the present invention have one or more ofthe following advantages. The dosage forms of the present invention arecapable of delivering greater amounts of drug to the desired environmentof use with greater efficiency using smaller amounts of swellingmaterials, and also result in lower amounts of residual drug than doconventional compositions. The compositions are also capable of higherdrug loading compared with conventional compositions. In addition, thecompositions begin delivering drug to the environment of use morequickly than do conventional osmotic controlled release dosage forms.The dosage forms are capable of rapidly delivering a low-solubility drugwithout the coating failing due to rupture as a result of excessivepressure within the core when the dosage form is introduced into anenvironment of use. The dosage forms are also capable of delivering alow-solubility drug in a solubilized form.

[0019] The foregoing and other objectives, features, and advantages ofthe invention will be more readily understood upon consideration of thefollowing detailed description of the invention, taken in conjunctionwith the accompanying drawing.

BRIEF DESCRIPTION OF THE DRAWING

[0020]FIG. 1 is a schematic drawing of a cross section of an exemplaryembodiment of a dosage form of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0021] The present invention provides a controlled release dosage formthat is specifically designed to provide controlled release of alow-solubility drug primarily by imbibition of water and extrusion ofdrug from the dosage form as opposed to primarily by diffusion. FIG. 1shows an exemplary dosage form 10 having a core 12 comprising adrug-containing composition 14 and a water-swellable composition 16. Thedrug-containing composition and the water-swellable composition occupyseparate regions in the core. By “separate regions” is meant that thetwo compositions occupy separate volumes, such that the two are notsubstantially mixed together. Of course, a small amount of intermixingof the compositions may occur where the compositions come in contactwith each other, for example, at the interface between two layers. Acoating 18 surrounds the core 12 and is water-permeable, water-insolubleand has one or more delivery ports 20 therethrough. In use, the core 12imbibes water through the coating 18 from the environment of use such asthe gastrointestinal (“GI”) tract. The imbibed water causes thewater-swellable composition 16 to swell, thereby increasing the pressurewithin the core 12. The imbibed water also increases the fluidity of thedrug-containing composition. The pressure difference between the core 12and the environment of use drives the release of the fluidizeddrug-containing composition 14. Because the coating 18 remains intact,the drug-containing composition 14 is extruded out of the core 12through the delivery port(s) 20 into the environment of use. Because thewater-swellable composition 16 contains no drug, almost all of the drugis extruded through the delivery port(s) 20, leaving very littleresidual drug.

[0022] The dosage form of the present invention releases the drug to anenvironment of use primarily by “extrusion” rather than by diffusion.The term “extrusion” as used herein is intended to convey an expulsionor forcing out of some or all of the drug through one or more deliveryports or pores in the coating to the exterior of the dosage form byhydrostatic forces, to be distinguished from delivery by a diffusionmechanism or by erosion of the mass of the device. The drug may bereleased primarily by extrusion either in the form of a suspension ofsolids in aqueous solution or the drug may be in solution, to the extentdissolution has taken place in the core 12.

[0023] Reference to the “release” of drug as used herein means (1)transport of drug from the interior of the dosage form to its exteriorsuch that it contacts the fluid within a mammal's GI tract followingdelivery or (2) tran sport of drug from the interior of the dosage formsuch that it contacts a test medium for evaluation of the dosage form byan in vitro test as described below. Reference to a “use environment”can thus be either to in vivo GI fluids or to an in vitro test medium.“Introduction” to a use environment includes either by ingestion orswallowing or use of implants or suppositories, where the useenvironment is in vivo, or being placed in a test medium where the useenvironment is in vitro.

Release Characteristics

[0024] An important attribute of the dosage forms of the presentinvention is the delivery of drug to a use environment in a controlledmanner. The dosage forms provide drug concentration release profilesthat meet the following criteria.

[0025] First, in some aspects of the present invention, the dosage formsstart releasing drug soon after introduction to the use environment.When a rapid onset of delivery is desired, preferably the dosage formsrelease at least 5 wt % of the drug, and more preferably at least 10 wt% of the drug within 2 hours after introduction to the use environment,where these percentages correspond to the mass of drug released from thecore relative to the total mass of drug originally present in the core.By quickly beginning the release of the drug, the dosage form shortensthe time required to achieve a maximum drug concentration in a useenvironment and increases the total amount of time during which the drugis in a use environment, resulting in increased absorption and greaterbioavailability.

[0026] Second, the dosage forms release the drug in a controlled manner,preferably at a substantially constant rate. Thus, the dosage formsrelease no more than about 60 wt % of the drug, and preferably no morethan about 50 wt % of the drug, into the use environment within 2 hoursafter introduction to the use environment.

[0027] Third, the rate of release of drug from the dosage form should besufficiently high to allow release of the drug within a time frame thatallows a substantial fraction of the drug delivered to be absorbed intothe blood stream. Specifically, the dosage forms release at least 60 wt% of the drug, and preferably at least 70 wt % of the drug to the useenvironment within 16 hours after introduction to the use environment.The inclusion of a fluidizing agent in the drug-containing compositionis particularly useful when more rapid delivery of drug to the useenvironment is desired. In particular, when it is desirable to deliverat least 70 wt % of the drug to the use environment within 12 hoursafter introduction thereto, the invention allows rapid drug releasewithout rupture or otherwise failure of the dosage form coating duringoperation.

[0028] Fourth, the dosage forms release a substantial amount of the drugcontained within the dosage form, leaving a relatively small residualamount of drug after 24 hours. Obtaining low residual amounts of drug isparticularly difficult when it is desired to deliver high doses oflow-solubility drug. The dosage forms of the present invention releaseat least 80 wt % of drug, preferably at least 90 wt %, and morepreferably at least 95 wt % of drug to the use environment within 24hours after introduction of the dosage form to the use environment.

[0029] An in vitro test may be used to determine whether a dosage formprovides a release profile within the scope of the present invention. Invitro tests are well known in the art. An example is a “residual test,”which is described below for sertraline HCl. The dosage form is firstplaced into a stirred USP type 2 dissoette flask containing 900 mL of abuffer solution simulating gastric environment (10 mM HCl, 100 mM NaCl,pH 2.0, 261 mOsm/kg) at 37° for 2 hours, then removed, rinsed withdeionized water, and transferred to a stirred USP type 2 dissoette flaskcontaining 900 mL of a buffer solution simulating the contents of thesmall intestine (6 mM KH₂PO₄, 64 mM KCl, 35 mM NaCl, pH 7.2, 210mOsm/kg). In both flasks, the dosage form is placed in a wire support tokeep the dosage form off of the bottom of the flask, so that allsurfaces are exposed to the moving release solution and the solutionsare stirred using paddles that rotate at a rate of 50 rpm. At each timeinterval, a single dosage form is removed from the solution, releasedmaterial is removed from the surface, and the dosage form cut in halfand placed in 100 mL of a recovery solution (1:1 wt/wt ethanol:water, pHadjusted to 3 with 0.1 N HCl), and vigorously stirred overnight atambient temperature to dissolve the drug remaining in the dosage form.Samples of the recovery solution containing the dissolved drug arefiltered using a Gelman Nylon® Acrodisc® 13, 0.45 μm pore size filter,and placed in a vial and capped. Residual drug is analyzed by HPLC. Drugconcentration is calculated by comparing UV absorbance of samples to theabsorbance of drug standards. The amount remaining in the tablets issubtracted from the total drug to obtain the amount released at eachtime interval.

[0030] An alternative in vitro test is a direct test, in which samplesof the dosage form are placed into a stirred USP type 2 dissoette flaskcontaining 900 mL of a receptor solution such as USP sodium acetatebuffer (27 mM acetic acid and 36 mM sodium acetate, pH 4.5) or 88 mMNaCl. Samples are taken at periodic intervals using a VanKel VK8000autosampling dissoette with automatic receptor solution replacement.Tablets are placed in a wire support as above, paddle height isadjusted, and the dissoette flasks stirred at 50 rpm at 37° C. Theautosampler dissoette device is programmed to periodically remove asample of the receptor solution, and the drug concentration is analyzedby HPLC using the procedure outlined above. Since the drug is usuallyextruded from the dosage form as a suspension in an entraining polymer,there is often a time lag between when the drug is released and when itis dissolved in the test medium, and thus, measured in the direct test.This time lag depends on the solubility of the drug, the test medium,and the ingredients of the drug-containing composition, but typically ison the order of 30 to 90 minutes.

[0031] Alternatively, an in vivo test may be used to determine whether adosage form provides a drug release profile within the scope of thepresent invention. However, due to the inherent difficulties andcomplexity of the in vivo procedure, it is preferred that in vitroprocedures be used to evaluate dosage forms even though the ultimate useenvironment is often the human GI tract. Drug dosage forms are dosed toa group of humans or dogs and drug release and drug absorption ismonitored either by (1) periodically withdrawing blood and measuring theserum or plasma concentration of drug or (2) measuring the amount ofdrug remaining in the dosage form following its exit from the anus(residual drug) or (3) both (1) and (2). In the second method, residualdrug is measured by recovering the tablet upon exit from the anus of thetest subject and measuring the amount of drug remaining in the dosageform using the same procedure described above for the in vitro residualtest. The difference between the amount of drug in the original dosageform and the amount of residual drug is a measure of the amount of drugreleased during the mouth-to-anus transit time. This test has limitedutility since it provides only a single drug release time point but isuseful in demonstrating the correlation between in vitro and in vivorelease.

[0032] In one in vivo method of monitoring drug release and absorption,the serum or plasma drug concentration is plotted along the ordinate(y-axis) against the blood sample time along the abscissa (x-axis). Thedata may then be analyzed to determine drug release rates using anyconventional analysis, such as the Wagner-Nelson or Loo-Riegelmananalysis. See also Welling, “Pharmacokinetics: Processes andMathematics” (ACS Monograph 185, Amer. Chem. Soc., Washington, D.C.,1986). Treatment of the data in this manner yields an apparent in vivodrug release profile.

Drug-containing Composition

[0033] Referring again to FIG. 1, The drug-containing composition 14 ofthe core 12 of the dosage form 10 includes at least a low-solubilitydrug and an entraining agent, and preferably additional excipients. Thedrug-containing composition occupies a separate, substantially distinctregion from the water-swellable composition, and comprises about 50 to90 wt % of the core, preferably 60 to 85 wt % of the core, and morepreferably greater than 70 wt % of the core. Preferably, thedrug-containing composition 14 is in contact with the coating 18 whichsurrounds the dosage form.

[0034] The drug may be virtually any beneficial therapeutic agent andmay comprise from 0.1 to 65 wt % of the drug-containing composition 14.In cases where the dose to be delivered is high, it is preferred thatthe drug comprise at least 35 wt % of the drug-containing composition14. The drug may be in any form, either crystalline or amorphous. Thedrug may also be in the form of a solid dispersion. The invention findsparticular utility when the drug is a “low-solubility drug.” In thiscontext, “low-solubility drug” generally means that the solubility issufficiently low that, during operation within a use environment, atleast a portion of the drug remains undissolved and therefore isdelivered as a suspension. In the small volume of a coated tablet, thedrug solubility and dose-to-aqueous solubility ratio must be quite highin order for all of the drug to dissolve and be delivered as a solution.Specifically, by “low-solubility drug” we mean that the drug is either“substantially water-insoluble” (which means that the drug has a minimumaqueous solubility at physiologically relevant pH (e.g., pH 1-8) of lessthan 0.01 mg/mL), or “sparingly water soluble,” that is, has a minimumaqueous solubility at physiologically relevant pH up to about 1 to 2mg/mL, or has even low to moderate aqueous solubility, having a minimumaqueous solubility at physiologically relevant pH as high as about 20 to40 mg/mL. In general, it may be said that the drug has a dose-to-aqueoussolubility ratio greater than 10 mL, and more typically greater than 100mL, where the drug solubility is the minimum value in mg/mL observed inany physiologically relevant aqueous solution (e.g., those with pHvalues between 1 and 8) including USP simulated gastric and intestinalbuffers and the dose is in mg. The drug may be employed in its neutral(e.g., free acid, free base or zwitterion) form, or in the form of itspharmaceutically acceptable salts as well as in anhydrous, hydrated, orsolvated forms, and pro drugs.

[0035] Preferred classes of drugs include, but are not limited to,antihypertensives, antidepressants, antianxiety agents, anticlottingagents, anticonvulsants, blood glucose-lowering agents, decongestants,antihistamines, antitussives, anti-inflammatories, antipsychotic agents,cognitive enhancers, cholesterol-reducing agents, cholesterol estertransfer protein inhibitors, high-density lipoprotein enhancers,antiobesity agents, autoimmune disorders agents, anti-impotence agents,antibacterial and antifungal agents, hypnotic agents, anti-Parkinsonismagents, antibiotics, antiviral agents, anti-neoplastics, barbituates,sedatives, nutritional agents, beta blockers, emetics, anti-emetics,diuretics, anticoagulants, cardiotonics, androgens, corticoids, anabolicagents, growth hormone secretagogues, anti-infective agents, coronaryvasodilators, carbonic anhydrase inhibitors, antiprotozoals,gastrointestinal agents, serotonin antagonists, anesthetics,hypoglycemic agents, dopaminergic agents, anti-Alzheimer's Diseaseagents, anti-ulcer agents, platelet inhibitors and glycogenphosphorylase inhibitors.

[0036] Specific examples of the above and other classes of drugs andtherapeutic agents deliverable by the invention are set forth below, byway of example only. Specific examples of antihypertensives includeprazosin, nifedipine, trimazosin, amlodipine, and doxazosin mesylate; aspecific example of an antianxiety agent is hydroxyzine; a specificexample of a blood glucose lowering agent is glipizide; a specificexample of an anti-impotence agent is sildenafil citrate; specificexamples of anti-neoplastics include chlorambucil, lomustine andechinomycin; specific examples of anti-inflammatory agents includebetamethasone, prednisolone, piroxicam, aspirin, flurbiprofen and(+)-N-{4-[3-(4fluorophenoxy)phenoxy]-2-cyclopenten-1-yl}-N-hyroxyurea; aspecific example of a barbituate is phenobarbital; specific examples ofantivirals include acyclovir, nelfinavir, and virazole; specificexamples of vitamins/nutritional agents include retinol and vitamin E;specific examples of a β-blocker include timolol and nadolol; a specificexample of an emetic is apomorphine; specific examples of a diureticinclude chlorthalidone and spironolactone; a specific example of ananticoagulant is dicumarol; specific examples of cardiotonic includedigoxin and digitoxin; specific examples of an androgen include17-methyltestosterone and testosterone; a specific example of a mineralcorticoid is desoxycorticosterone; a specific example of a steroidalhypnotic/anesthetic is alfaxalone; specific examples of an anabolicagent include fluoxymesterone and methanstenolone; specific examples ofantidepression agents include fluoxetine, pyroxidine, venlafaxine,sertraline, paroxetine, sulpiride,[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(lethylpropyl)-amineand 3,5-dimethyl-4-(3′-pentoxy)-2-(2′,4′,6′-trimethylphenoxy)pyridine;specific examples of an antibiotic include ampicillin and penicillin G;specific examples of an anti-infective include benzalkonium chloride andchlorhexidine; specific examples of a coronary vasodilator includenitroglycerin and mioflazine; a specific example of a hypnotic isetomidate; specific examples of a carbonic anhydrase inhibitor includeacetazolamide and chlorzolamide; specific examples of an antifungalinclude econazole, terconazole, fluconazole, voriconazole andgriseofulvin; a specific example of an antiprotozoal is metronidazole; aspecific example of an imidazole-type anti-neoplastic is tubulazole;specific examples of an anthelmintic agent include thiabendazole,oxfendazole and morantel; specific examples of an antihistaminic includeastemizole, levocabastine, cetirizine, and cinnarizine; a specificexample of a decongestant is pseudoephedrine; specific examples ofantipsychotics include fluspirilene, penfluridole, risperidone andziprasidone; specific examples of a gastrointestinal agent includeloperamide and cisapride; specific examples of a serotonin antagonistinclude ketanserin and mianserin; a specific example of an anesthetic islidocaine; a specific example of a hypoglycemic agent is acetohexamide;a specific example of an anti-emetic is dimenhydrinate; a specificexample of an antibacterial is cotrimoxazole; a specific example of adopaminergic agent is L-DOPA; specific examples of anti-Alzheimer agentsare THA and donepezil; a specific example of an anti-ulcer agent/H2antagonist is famotidine; specific examples of a sedative/hypnoticinclude chlordiazepoxide and triazolam; a specific example of avasodilator is alprostadil; a specific example of a platelet inhibitoris prostacyclin; specific examples of an ACE inhibitor/antihypertensiveinclude enalaprilic acid and lisinopril; specific examples of atetracycline antibiotic include oxytetracycline and minocycline;specific examples of a macrolide antibiotic include azithromycin,clarithromycin, erythromycin and spiramycin; specific examples ofglycogen phosphorylase inhibitors include[R-(R*S*)]-5-Chloro-N-[2-hydroxy-3-{methoxymethylamino}-3-oxo-1-(phenylmethyl)-propyl]-1H-indole-2-carboxamideand 5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-(2R)-hydroxy-3((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-oxypropyl]amide.

[0037] Further examples of drugs deliverable by the invention are theglucose-lowering drug chlorpropamide, the anti-fungal fluconazole, theanti-hypercholesterodemic atorvastatin, the antipsychotic thiothixene,the anxiolytics hydroxyzine and doxepin, the anti-hypertensiveamlodipine, the antiinflammatories piroxicam, celicoxib, valdicoxib andcarprofen, and the antibiotics carbenicillin indanyl, bacampicillin,troleandomycin, and doxycycline.

[0038] In an alternative embodiment, the drug is present in the form ofa solid, amorphous dispersion. By solid, amorphous dispersion is meantthat the drug is dispersed in a polymer so that a major portion of thedrug is in a substantially amorphous or non-crystalline state, and itsnon-crystalline nature is demonstrable by x-ray diffraction analysis orby differential scanning calorimetry. The dispersion may contain fromabout 5 to 90 wt % drug, preferably 10 to 70 wt %. The polymer isaqueous-soluble and inert, and is preferably concentration-enhancing.Suitable polymers and methods for making solid amorphous dispersions aredisclosed in commonly assigned U.S. patent application Ser. Nos.09/459,059 and 09/495,061, the relevant disclosures of which areincorporated by reference. Suitable dispersion polymers includeionizable and non-ionizable cellulosic polymers, such as celluloseesters, cellulose ethers, and cellulose esters/ethers; and vinylpolymers and copolymers having substituents selected from the groupconsisting of hydroxyl, alkylacyloxy, and cyclicamido, such as polyvinylpyrrolidone, polyvinylalcohol, copolymers of polyvinyl pyrrolidone andpolyvinyl acetate. Particularly preferred polymers includehydroxypropylmethyl cellulose acetate succinate (HPMCAS), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl methyl cellulose phthalate(HPMCP), cellulose acetate phthalate (CAP), cellulose acetatetrimellitate (CAT), and polyvinyl pyrrolidone (PVP). Most preferred areHPMCAS, HPMCP, CAP and CAT.

[0039] The drug-containing composition 14 must include an entrainingagent. The use of an entraining agent is necessitated by thelow-solubility drug, which due to its low-solubility does not dissolvesufficiently within the core 12 to be extruded in the absence of anentraining agent. The entraining agent suspends or entrains the drug soas to aid in the delivery of the drug through the delivery port(s) 20 tothe environment of use. While not wishing to be bound by any particulartheory, it is believed that upon imbibing water into the dosage form,the entraining agent imparts sufficient viscosity to the drug-containingcomposition to allow it to suspend or entrain the drug, while at thesame time remaining sufficiently fluid to allow the entraining agent topass through the delivery port(s) 20 along with the drug. It has beenfound that there is a good correlation between the usefulness of amaterial as an entraining agent and the viscosity of an aqueous solutionof the material. The entraining agent generally is a material that hashigh water solubility and in operation forms aqueous solutions withviscosities of at least 50 centipoise (cp) and preferably aqueoussolutions with viscosities of 200 cp or greater.

[0040] The amount of the entraining agent present in the drug-containingcomposition may range from about 20 wt % to about 98 wt % of thedrug-containing composition. The entraining agent may be a singlematerial or a mixture of materials. Examples of such materials includepolyols, and oligomers of polyethers, such as ethylene glycol oligomersor propylene glycol oligomers. In addition, mixtures of polyfunctionalorganic acids and cationic materials such as amino acids or multivalentsalts, such as calcium salts may be used. Of particular utility arepolymers such as polyethylene oxide (PEO), polyvinyl alcohol, PVP,cellulosics such as hydroxyethyl cellulose (HEC), hydroxypropylcellulose(HPC), HPMC, methyl cellulose (MC), carboxy methyl cellulose (CMC),carboxyethylcellulose (CEC), gelatin, xanthan gum or any otherwater-soluble polymer that forms an aqueous solution with a viscositysimilar to that of the polymers listed above. An especially preferredentraining agent is non-crosslinked PEO or mixtures of PEO with theother materials listed above.

[0041] When the low-solubility drug and a polymeric entraining agentmake up about 80 wt % or more of the drug-containing composition, thenthe entraining agent, should have a sufficiently low molecular weightthat it becomes sufficiently fluid so that both the drug and entrainingagent can be rapidly extruded from the dosage form, instead of swellingand rupturing the water-permeable coating that surrounds the dosageform. Thus, for example, when PEO is the drug-entraining agent, it isgenerally preferred that it have a molecular weight of from about100,000 to about 300,000 daltons. (References to molecular weights ofpolymers herein and in the claims are to average molecular weights.)

[0042] When the low-solubility drug and the entraining agent make upless than about 80 wt % of the drug-containing composition, a smallerportion of a more viscous entraining agent is preferred. For example,when the entraining agent is PEO, a lower fraction of a higher molecularweight of PEO from about 500,000 to 800,000 daltons may be used. Thus,there is an inverse relationship between the preferred PEO molecularweight and the weight fraction of the drug-containing composition thatis drug and entraining agent. Thus, as the weight fraction decreasesfrom about 0.9 to about 0.8, to about 0.7, to about 0.6, the preferredPEO molecular weight increases from about 200,000 daltons to about400,000 daltons, to about 600,000 daltons, to about 800,000 daltons,respectively, and the weight fraction of entraining agentcorrespondingly decreases (the weight fraction of drug being relativelyconstant). It should be noted that for a particular formulation, theoptimum PEO molecular weight for the entraining agent may vary higher orlower than those values by 20% to 50%. Likewise, when selecting anappropriate molecular weight of other polymeric entraining agents suchas HEC, HPC, HPMC, or MC, as the weight fraction of entraining agent inthe drug-containing composition is reduced, a higher molecular weightfor the entraining agent is generally preferred.

[0043] In one embodiment of the invention, the drug-containingcomposition comprises a swelling agent in addition to the low-solubilitydrug and the drug-entraining agent. The swelling agent is generally awater-swellable polymer that substantially expands in the presence ofwater. Inclusion of even a small amount of such a swellable polymer cansignificantly enhance the onset, rate, and completeness of drugdelivery. The degree of swelling of a swelling agent can be assessed bycompressing particles of the swelling agent in a press to form a compactof the material having a “strength” ranging from 3 to 16 Kp/cm², wherestrength is the hardness of the compact in Kp as measured with aSchleuniger Tablet Hardness Tester, model 6D, divided by its maximumcross-sectional area normal to the direction of force in cm². Forexample, about 500 mg of a swelling agent can be compressed in a{fraction (13/32)}-inch die using an “f press.” The swelling of acompact is measured by placing it between two porous glass frits in aglass cylinder and contacting it with a physiologically relevant testmedium, such as simulated gastric or intestinal buffer, or water. Thevolume of the water-swollen compact after 16 to 24 hours contact withthe test medium divided by its initial volume is termed the “swellingratio” of the swelling agent. Generally, swelling agents suitable forinclusion in the drug layer are those water-swellable polymers that haveswelling ratios, when water is the test medium, of at least 3.5,preferably greater than 5.

[0044] A preferred class of swelling agents comprises ionic polymers.Ionic polymers are generally polymers that have a significant number offunctional groups that are substantially ionized in an aqueous solutionover at least a portion of the physiologically relevant pH range 1 to 8.Such ionizable functional groups include carboxylic acids and theirsalts, sulfonic acids and their salts, amines and their salts, andpyridine salts. To be considered an ionic polymer, the polymer shouldhave at least 0.5 milli-equivalents of ionizable functional groups pergram of polymer. Such ionic polymer swelling agents include sodiumstarch glycolate, sold under the trade name EXPLOTAB, and croscarmellosesodium, sold under the trade name AC-DI-SOL.

[0045] In one embodiment of the invention in which the drug-containingcomposition comprises a low-solubility drug, a drug-entraining agent,and a swelling agent, the swelling agent is present in an amount rangingfrom about 2 to about 20 wt % of the drug-containing composition 14. Inother embodiments of the invention, the swelling agent is optionallypresent in an amount ranging from 0 to about 20 wt %.

[0046] In another embodiment of the present invention, thedrug-containing composition further comprises a fluidizing agent. Asused herein, a “fluidizing agent” is a water-soluble compound thatallows the drug-containing composition to rapidly become fluid uponimbibing water when the dosage form is introduced into a useenvironment. Rapid fluidization of the drug-containing compositionallows the composition to be extruded from the dosage form without abuild-up of excessive pressure. This results in a relatively short timelag. That is, the time between introduction of the dosage form into theenvironment of use and the onset of drug delivery is relatively short.In addition, the inclusion of a fluidizing agent reduces the pressurewithin the core and thus reduces the risk of failure of the coating thatsurrounds the core of the dosage form. This is particularly importantwhen a relatively rapid rate of drug release is desired, necessitatingthe use of a highly water-permeable coating that conventionally isrelatively thin and weak. (By a rapid rate of release is generally meantthat greater than 70 wt % of the low-solubility drug originally presentin the dosage form is released within 12 hours of the time the dosageform is introduced into the use environment.)

[0047] The fluidizing agent can be essentially any water-solublecompound that rapidly increases the fluidity of the drug-containingcomposition when water is imbibed into the core. Such compoundsgenerally have aqueous solubilities of at least 30 mg/mL and generallyhave a relatively low molecular weight (less than 10,000 daltons) suchthat upon imbibing a given quantity of water, the drug-containingcomposition rapidly becomes more fluid relative to a similardrug-containing composition that does not include the fluidizing agent.By more fluid is meant that the pressure required to extrude the drugthrough the delivery port(s) is lower than a similar composition withoutthe fluidizing agent. This increased fluidity can be temporary, meaningthat the increased fluidity occurs for only a short time afterintroduction of the dosage form to a use environment (e.g., 2 hours), orthe increased fluidity can occur over the entire time the dosage form isin the use environment. Exemplary fluidizing agents are sugars, organicacids, amino acids, polyols, salts, and low-molecular weight oligomersof water-soluble polymers. Exemplary sugars are glucose, sucrose,xylitol, fructose, lactose, mannitol, sorbitol, maltitol, and the like.Exemplary organic acids are citric acid, lactic acid, ascorbic acid,tartaric acid, malic acid, fumaric, and succinic acid. Exemplary aminoacids are alanine and glycine. Exemplary polyols are propylene glycoland sorbitol. Exemplary oligomers of low-molecular weight polymers arepolyethylene glycols with molecular weights of 10,000 daltons or less.Particularly preferred fluidizing agents are sugars and organic acids.Such fluidizing agents are preferred as they often improve tableting andcompression properties of the drug-containing composition relative toother fluidizing agents such as inorganic salts or low-molecular weightpolymers.

[0048] In order for the fluidizing agent to rapidly increase thefluidity of the drug-containing composition at low water levels in thecore 12 of the dosage form, the fluidizing agent must generally bepresent in an amount such that it makes up at least about 10 wt % of thedrug-containing composition 14. To ensure that the drug-containingcomposition 14 does not become so fluid such that the drug-entrainingagent cannot properly entrain or suspend the drug, particularly longafter (12 hours or longer) introduction of the dosage form into the useenvironment, the amount of fluidizing agent generally should not exceedabout 60 wt % of the drug-containing composition. In addition, asmentioned above, when a fluidizing agent is included, a drug-entrainingagent with a higher molecular weight and correspondingly higherviscosity is generally included in the drug-containing composition, butat a lower level. Thus, for example, when the drug-containingcomposition comprises about 20 to 30 wt % of the low-solubility drug andabout 30 wt % of a fluidizing agent such as a sugar, about 20 to 50 wt %of a high molecular weight polymer such as PEO with a molecular weightof about 500,000 to 800,000 daltons is preferable to a lower molecularweight PEO.

[0049] The drug-containing composition 14 may further includesolubility-enhancing agents that promote the aqueous solubility of thedrug, present in an amount ranging from about 0 to about 30 wt % of thedrug-containing composition 14. Examples of suitablesolubility-enhancing agents include surfactants; pH control agents suchas buffers, organic acids and organic acid salts and organic andinorganic bases; glycerides; partial glycerides; glyceride derivatives;polyhydric alcohol esters; PEG and PPG esters; polyoxyethylene andpolyoxypropylene ethers and their copolymers; sorbitan esters;polyoxyethylene sorbitan esters; carbonate salts; and cyclodextrins.

[0050] There are a variety of factors to consider when choosing anappropriate solubilizing agent for a drug. The solubilizing agent shouldnot interact adversely with the drug. In addition, the solubilizingagent should be highly efficient, requiring minimal amounts to effectthe improved solubility. It is also desired that the solubilizing agenthave a high solubility in the use environment. For acidic, basic, andzwitterionic drugs, organic acids, organic acid salts, and organic andinorganic bases and base salts are known to be useful solubilizingagents. It is desired that these compounds have a high number ofequivalents of acid or base per gram. The selection of solubilizingagent will therefore be highly dependent on the properties of the drug.

[0051] A preferred class of solubilizers for basic drugs is organicacids. Since basic drugs are solubilized by protonation, and since thesolubility of basic drugs in an aqueous environment of pH 5 or higher isreduced and often may reach an extremely low value by pH 7.5 (as in thecolon), it is believed that addition of an organic acid to the dosageform for delivery to the use environment with such drugs assists insolubilization and hence absorption of the drug. An exemplary basic drugis sertraline, which has moderate solubility at low pH, low solubilityat pH values above 5 and extremely low solubility at pH of about 7.5.Another example of a basic drug that may benefit from an acidicsolubilizer is ziprasidone. Even a slight decrease in the pH of theaqueous solution at high pH may result in dramatic increases in thesolubility of basic drugs. In addition to simply lowering the pH, thepresence of organic acids and their conjugate bases also raises thesolubility at a given pH if the conjugate base salt of the basic drughas a higher solubility than the neutral form or the chloride salt ofthe drug.

[0052] It has been found that a preferred subset of organic acidsmeeting such criteria consists of citric, succinic, fumaric, adipic,malic and tartaric acids. The table below gives properties of theseorganic acids. Of these, fumaric and succinic are especially preferredwhen a high ratio of equivalents of acid per gram is desired. Inaddition, citric, malic, and tartaric acid have the advantage ofextremely high water solubility. Succinic acid offers a combination ofboth moderate solubility and a high acid equivalent per gram value.Thus, the use of a highly soluble organic acid serves multiple purposes:it improves the solubility of the basic drug, particularly when the useenvironment is at a pH above about 5 to 6; it makes the drug-containingcomposition more hydrophilic so that it readily wets; and it dissolves,lowering the viscosity of the layer rapidly, thus acting as a fluidizingagent. Thus, by accomplishing multiple functions with a singleingredient, additional space is available for the low-solubility drugwithin the drug-containing composition. Properties of Organic AcidSolubilizing Agents Equivalents Water Organic Value Solubility Acid(mEq/g) (mg/mL) Fumaric 17.2 11 Succinic 16.9 110 Citric 15.6 >2000Malic 14.9 1750 Adipic 13.7 45 Tartaric 13.3 1560

[0053] For acidic drugs, solubility is increased as pH increases.Exemplary classes of solubilizers for acidic drugs include alkylating orbuffering agents and organic bases. It is believed that addition of analkylating agent or organic base to the dosage form assists insolubilization and hence absorption of the drug. Examples of alkylatingor buffering agents include potassium citrate, sodium bicarbonate,sodium citrate, dibasic sodium phosphate, and monobasic sodiumphosphate. Examples of organic bases include meglumine, eglumine,monoethanol amine, diethanol amine, and triethanol amine.

[0054] The drug-containing composition 14 may optionally include aconcentration-enhancing polymer that enhances the concentration of thedrug in a use environment relative to control compositions that are freefrom the concentration-enhancing polymer. The concentration-enhancingpolymer should be inert, in the sense that it does not chemically reactwith the drug in an adverse manner, and should have at least somesolubility in aqueous solution at physiologically relevant pHs (e.g.1-8). Almost any neutral or ionizable polymer that has an aqueoussolubility of at least 0.1 mg/mL over at least a portion of the pH rangeof 1-8 may be suitable. Especially useful polymers are those discussedabove for forming solid-amorphous dispersions of the drug with apolymer. Preferred polymers include hydroxypropylmethyl celluloseacetate succinate (HPMCAS), hydroxypropylmethyl cellulose (HPMC),hydroxy propylmethyl cellulose phthalate (HPMCP), cellulose acetatephthalate (CAP), cellulose acetate trimellitate (CAT), andpolyvinylpyrrolidone (PVP). More preferred polymers included HPMCAS,HPMCP, CAP and CAT.

[0055] Without being bound by any particular theory or mechanism ofaction, it is believed that the concentration-enhancing polymer preventsor retards the rate at which a drug, delivered from the dosage form andpresent in the use environment at a concentration greater than itsequilibrium value, approaches its equilibrium concentration. Thus, whenthe dosage form is compared to a control dosage form that is identicalexcept for the absence of the concentration-enhancing polymer, theconcentration-enhancing polymer-containing dosage form provides, atleast for a short time period, a greater concentration of dissolved drugin the use environment. Appropriate drug forms andconcentration-enhancing polymers are discussed in commonly assignedpending patent application “Pharmaceutical Compositions ProvidingEnhanced Drug Concentrations” filed Dec. 23, 1999 concurrently herewith,U.S. provisional patent application No. 60/171,841, the relevantportions of which are herein incorporated by reference.

[0056] The drug-containing composition 14 may optionally includeexcipients that promote drug stability. Examples of such stabilityagents include pH control agents such as buffers, organic acids andorganic acid salts and organic and inorganic bases and base salts. Theseexcipients can be the same materials listed above for use assolubilizers or fluidizing agents. Another class of stability agents isantioxidants, such as butylated hydroxy toluene (BHT), butylatedhydroxyanisole (BHA), vitamin E, and ascorbyl palmitate. The amount ofstability agent used in the drug-containing composition should besufficient to stabilize the low-solubility drug. For pH control agentssuch as organic acids, the stability agent, when present, may range from0.1 to 20 wt % of the drug-containing composition. Note that in someformulations, antioxidants such as BHT can lead to discoloration of thedosage form. In these cases, the amount of antioxidant used should beminimized so as to prevent discoloration. The amount of antioxidant usedin the drug-containing composition generally ranges from 0 to 1 wt % ofthe drug-containing composition.

[0057] Finally, the drug-containing composition 14 may also includeother conventional excipients, such as those that promote performance,tableting or processing of the dosage form. Such excipients includetableting aids, surfactants, water-soluble polymers, pH modifiers,fillers, binders, pigments, osmagents, disintegrants and lubricants.Exemplary excipients include microcrystalline cellulose; metallic saltsof acids such as aluminum stearate, calcium stearate, magnesiumstearate, sodium stearate, and zinc stearate; fatty acids, hydrocarbonsand fatty alcohols such as stearic acid, palmitic acid, liquid paraffin,stearyl alcohol, and palmitol; fatty acid esters such as glyceryl (mono-and di-) stearates, triglycerides, glyceryl (palmitic stearic) ester,sorbitan monostearate, saccharose monostearate, saccharosemonopalmitate, and sodium stearyl fumarate; alkyl sulfates such assodium lauryl sulfate and magnesium lauryl sulfate; polymers such aspolyethylene glycols, polyoxyethylene glycols, andpolytetrafluoroethylene; and inorganic materials such as talc anddicalcium phosphate. In a preferred embodiment, the drug-containingcomposition 14 contains a lubricant such as magnesium stearate.

Water-swellable Composition

[0058] Referring again to FIG. 1, the dosage form further comprises awater-swellable composition 16. The water-swellable composition greatlyexpands as it imbibes water through the coating 18 from the useenvironment. As it expands, the water-swellable composition increasesthe pressure within the core 12, causing extrusion of the fluidizeddrug-containing composition through the port(s) 20 into the environmentof use. To maximize the amount of drug present in the dosage form and toensure that the maximum amount of drug is released from the dosage formso as to minimize residual drug, the water-swellable composition shouldhave a swelling ratio of at least about 2, preferably 3.5, and morepreferably 5.

[0059] The water-swellable composition 16 comprises a swelling agent inan amount ranging from about 30 to 100 wt % of the water-swellablecomposition 16. The swelling agent is generally a water-swellablepolymer that greatly expands in the presence of water. As discussedabove in connection with the swelling agent of the drug-containingcomposition, the degree of swelling of a swelling agent, or thewater-swellable composition itself, can be assessed by measuring itsswelling ratio.

[0060] Suitable swelling agents for the water-swellable composition aregenerally hydrophilic polymers that have swelling ratios of about 2.0 orgreater. Exemplary hydrophilic polymers include polyoxomers such as PEO,cellulosics such as HPMC and HEC, and ionic polymers. In general, themolecular weight of water swellable polymers chosen for the swellingagent is higher than that of similar polymers used as entraining agentssuch that, at a given time during drug release, the water-swellablecomposition 16 after imbibing water tends to be more viscous, lessfluid, and more elastic relative to the drug-containing composition 14.In some cases the swelling agent may be even substantially or almostentirely water insoluble such that when partially water swollen duringoperation, it may constitute a mass of water-swollen elastic particles.Generally, the swelling agent is chosen such that, during operation, thewater-swellable composition 16 generally does not substantially intermixwith the drug-containing composition 14, at least prior to extruding amajority of the drug-containing composition 14. Thus, for example, whenPEO is the swelling agent used in the water-swellable composition 16, amolecular weight of about 800,000 daltons or more is preferred and morepreferably a molecular weight of 3,000,000 to 8,000,000 daltons.

[0061] A preferred class of swelling agents is ionic polymers, describedabove for use in various embodiments of the drug-containing composition14. Exemplary ionic polymer swelling agents include sodium starchglycolate, sold under the trade name EXPLOTAB, croscarmellose sodium,sold under the trade name AC-DI-SOL, polyacrylic acid, sold under thetrade name CARBOBOL, and sodium alginate sold under the trade nameKELTONE.

[0062] The water-swellable composition may optionally further compriseosmotically effective agents, often referred to as “osmogens” or“osmagents.” The amount of osmagent present in the water-swellablecomposition may range from about 0 to about 40 wt % of thewater-swellable composition. Typical classes of suitable osmagents arewater-soluble salts and sugars that are capable of imbibing water tothereby effect an osmotic pressure gradient across the barrier of thesurrounding coating. The osmotic pressure of a material can becalculated using the van't Hoff equation. (See, e.g., Thermodynamics, byLewis and Randall). By “osmotically effective agent” is meant theinclusion of a material with low enough molecular weight, high enoughsolubility, and sufficient mass in the water-swellable composition thatupon imbibing water from the use environment it forms an aqueoussolution within the interior of the tablet such that its osmoticpressure exceeds that of the use environment, thereby providing anosmotic pressure driving force for permeation of water from the useenvironment into the tablet core. Typical useful osmagents includemagnesium sulfate, magnesium chloride, calcium chloride, sodiumchloride, lithium chloride, potassium sulfate, sodium carbonate, sodiumsulfite, lithium sulfate, potassium chloride, sodium sulfate,d-mannitol, urea, sorbitol, inositol, raffinose, sucrose, glucose,fructose, lactose, and mixtures thereof.

[0063] In one embodiment of the invention, the water-swellablecomposition 16 is substantially free from an osmotically effectiveagent, meaning that there is either a sufficiently small amount ofosmagent or that any osmagent present has sufficiently low solubility soas not to increase the osmotic pressure of the water-swellablecomposition 16 substantially beyond that of the use environment. Inorder for the dosage form to provide satisfactory release of drug in theabsence of an osmagent in the water-swellable composition 16, and whenthe water-swellable polymer is not an ionic polymer, the dosage formshould have a coating that is highly permeable to water. Suchhigh-permeability coatings are described below. When the water-swellablecomposition 16 is substantially free of an osmotically effective agent,the water swellable composition preferably contains a substantialquantity, typically at least 10 wt % and preferably at least 50 wt %, ofa highly swelling polymer such as sodium starch glycolate or sodiumcroscarmellose. As described earlier, highly swelling materials can beidentified by measuring the “swelling ratio” of the material formed intoa compact using the method described previously.

[0064] The release of a low-solubility drug relatively quickly withoutthe inclusion of an osmagent in the water-swellable composition is asurprising result, since conventional wisdom in the art has held thatosmagents should be included in the water-swellable composition toachieve good performance. Circumventing the need for inclusion of anosmagent provides several advantages. One advantage is that the spaceand weight which would otherwise be occupied by osmagent may be devotedto drug, thus permitting an increase in the amount of drug within thedosage form. Alternatively, the overall size of the dosage form may bedecreased. In addition, eliminating the osmagent simplifies the processfor manufacture of the dosage form, since the water-swellablecomposition 16 may omit the step of including an osmagent.

[0065] In one embodiment of the invention, the water swellablecomposition 16 comprises a swelling agent and a tableting aid. Thepreferred swelling agents (e.g., those that are highly swelling) aredifficult to compress to a hardness suitable for use in the dosage form.However, it has been found that adding a tableting aid to thewater-swellable composition in the amount of 5 to 50 wt % of thewater-swellable composition 16 results in a material that compresses toa hardness suitable for use in the dosage form. At the same timeinclusion of a tableting aid can adversely affect the swelling ratio ofthe water-swellable composition 16. Thus, the quantity and type oftableting aid used must be carefully selected. In general, hydrophilicmaterials with good compression properties should be used. Exemplarytableting aids include sugars such as lactose, in particular spray-driedversions sold under the trade name FASTFLOW LACTOSE, or xylitol,polymers such as microcrystalline cellulose, HPC, MC or HPMC. Preferredtableting aids are microcrystalline cellulose, both standard grades soldunder the trade name AVICEL and silicified versions sold under the tradename PROSOLV and HPC. The amount of tableting aid is chosen to besufficiently high so that the core 12 compresses well yet sufficientlylow so that the water-swellable composition 16 still has a swellingratio of at least 2, preferably 3.5, more preferably greater than 5.Typically, the amount is at least 20 but less than 60 wt %.

[0066] It is further desired that the mixture of swelling agent andtableting aid result in a material that has a “strength” of at least 3Kiloponds (Kp)/cm², and preferably at least 5 Kp/cm². Here, “strength”is the fracture force, also known as the core “hardness,” required tofracture a core 12 formed from the material, divided by the maximumcross-sectional area of the core 12 normal to that force. In this test,the fracture force is measured using a Schleuniger Tablet HardnessTester, model 6D. Both the compressed water-swellable composition 16 andresulting core 12 should have a strength of at least 3 Kp/cm², andpreferably at least 5 Kp/cm².

[0067] In a preferred embodiment, the water-swellable composition 16comprises a mixture of swelling agents in addition to a tableting aid.For example, the swelling agent croscarmellose sodium can be compressedinto a compact with higher strength than the swelling agent sodiumstarch glycolate. However, the swelling ratio of croscarmellose sodiumis lower than that of sodium starch glycolate. A water-swellablecomposition 16 with the desired combination of high swelling ratio andhigh strength can be formed using a mixture comprising 15 to 40 wt %sodium starch glycolate, 50 to 70 wt % croscarmellose sodium, and 5 to20 wt % of the tableting aid microcrystalline cellulose.

[0068] The water-swellable composition 16 may also includesolubility-enhancing agents or excipients that promote stability,tableting or processing of the dosage form of the same types mentionedabove in connection with the drug-containing composition. However, it isgenerally preferred that such excipients comprise a minor portion of thewater-swellable composition 16. In one preferred embodiment, thewater-swellable composition 16 contains a lubricant such as magnesiumstearate.

The Core

[0069] The core 12 may be any known tablet that can be formed by anextrusion or compression process and be subsequently coated and utilizedfor delivery of drug to a mammal. The tablet can generally range in sizefrom about 1 mm to about 10 cm for its longest dimension. The maximumsize of the tablet will be different for different animal species. Itcan have essentially any shape such that its aspect ratio, defined asthe tablet's longest dimension divided by the tablet's shortestdimension, ranges from about 1 to about 5. It is generally preferredthat the dimension of the tablet in the direction that the center ofmass of the drug-containing layer 14 moves when in the process of beingextruded from the dosage form divided by the longest dimension normal tothis direction of motion be greater than about 0.5. In addition, thedosage form may comprise two or more relatively small tablets containedin a relatively large container such as a capsule.

[0070] Exemplary core 12 shapes are spheres, ellipsoids, cylinders,capsule or caplet shapes and any other known shape. The core 12,following coating, can comprise the entire or a portion of the dosageform. The final dosage form can be for oral, rectal, vaginal,subcutaneous, or other known method of delivery into the environment ofuse. When the dosage form 10 is intended for oral administration to ahuman, the core 12 generally has an aspect ratio of about 3 or less, alongest dimension of about 2 cm or less and a total weight of about 1.5g or less and preferably a total weight of about 1.0 g or less.

[0071] To form the dosage form, the ingredients comprising thedrug-containing composition 14 and the water-swellable composition 16are first mixed or blended using processes known in the art. See forexample, Lachman, et al., “The Theory and Practice of IndustrialPharmacy” (Lea & Febiger, 1986). For example, a portion of theingredients of the drug-containing composition 14 can first be blended,then wet granulated, dried, milled, and then blended with additionalexcipients prior to tableting. Similar processes can be used to form thewater-swellable composition.

[0072] Once the materials are properly mixed, the core 12 is formedusing procedures known in the art, such as compression or extrusion. Forexample, to form cores in the form of tablets, the desired amount ofdrug-containing composition 14 is placed in a tablet press and leveledby lightly tamping with the press. The desired amount of water-swellablecomposition 16 is then added, and the tablet formed by compression.Alternatively, the water-swellable composition may be added to thetablet press first, followed by the drug-containing composition. Theamount of force used to compress the tablet core will depend on the sizeof the dosage form, as well as the compressibility and flowcharacteristics of the compositions. Typically, a pressure is used thatresults in a tablet with a strength of 3 to 20 Kp/cm².

The Coating

[0073] Following formation of the core 12, coating 18 is applied.Coating 18 should have both a sufficiently high water permeability thatthe drug can be delivered within the desired time frame, and highstrength, while at the same time be easily manufactured. A waterpermeability is chosen to control the rate at which water enters thecore, thus controlling the rate at which drug is delivered to the useenvironment. Where a high dose of a low-solubility drug is required, thelow solubility and high dose combine to make it necessary to use a highpermeability coating to achieve the desired drug release profile whilekeeping the tablet acceptably small. High strength is required to ensurethe coating does not burst when the core swells as it imbibes water,leading to an uncontrolled delivery of the core contents to the useenvironment. The coating must be easily applied to the dosage form withhigh reproducibility and yield. Furthermore, the coating must benon-dissolving and non-eroding during release of the drug-containingcomposition, generally meaning that it be sufficiently water-insolublethat drug is substantially entirely delivered through the deliveryport(s) 20, in contrast to delivery via permeation through coating 18.

[0074] As described above, the coating 18 is highly water-permeable toallow rapid imbibition of water into core 12 and as a result a rapidrelease of the drug-containing composition 14. A relative measure of thewater permeability of the coating can be made by conducting thefollowing experiment. Finished dosage forms are placed in an opencontainer which is in turn placed in an environmental chamber held at aconstant temperature of 40° C. and a constant relative humidity of 75%.The initial rate of weight gain of the dry dosage forms, determined byplotting the weight of the dosage form versus time, divided by thesurface area of the dosage form yields a value termed “water flux(40/75).” The water flux (40/75) for a dosage form has been found to bea useful relative measure of the water permeabilities of coatings. Forthe dosage forms of one embodiment of the present invention, inparticular when a rapid release of the drug is desired, the coatingshould have a water flux (40/75) value of at least 1.0×10⁻³ gm/hr·cm²,and preferably at least 1.3×10⁻³ gm/hr·cm².

[0075] As mentioned, the coating should also have a high strength toensure the coating 18 does not burst when the core swells due toimbibition of water from the use environment. A relative measure ofcoating strength can be made by conducting the following experiment thatmeasures the “durability” of the coating. Finished tablets are placedinto an aqueous medium for 10 to 24 hours, allowing the core to imbibewater, swell, and release drug to the media. The swollen dosage form canthen be tested in a hardness tester, such as a Model 6D Tablet Testermanufactured by Schleuniger Pharmatron, Inc. The dosage form is placedinto the tester so that its delivery port(s) (20) faces one side of thecompression plates. The force, in Kp, required to rupture the coating isthen measured. The durability of the coating is then calculated bydividing the measured rupture force by the maximum cross-sectional areaof the dosage form normal to the applied force. In one embodiment of thepresent invention, the coating should have a durability of at least 1Kp/cm², preferably at least 2 Kp/cm², and most preferably at least 3Kp/cm². Coatings with this or greater durability ensure virtually noburst tablets when the dosage forms are tested in vivo.

[0076] Coatings with these characteristics can be obtained usinghydrophilic polymers such as plasticized and unplasticized celluloseesters, ethers, and ester-ethers. Particularly suitable polymers includecellulose acetate (“CA”), cellulose acetate butyrate, and ethylcellulose. A particularly preferred set of polymers are celluloseacetates having acetyl contents of 25 to 42%. A preferred polymer is CAhaving an acetyl content of 39.8%, and specifically, CA 398-10manufactured by Eastman of Kingsport, Tenn., having an average molecularweight of about 40,000 daltons. Another preferred CA having an acetylcontent of 39.8% is high molecular weight CA having an average molecularweight greater than about 45,000, and specifically, CA 398-30 (Eastman)reported to have an average molecular weight of 50,000 daltons. The highmolecular weight CA provides superior coating strength, which allowsthinner coatings and thus higher permeability.

[0077] Coating is conducted in conventional fashion by first forming acoating solution and then coating by dipping, fluidized bed coating, orpreferably by pan coating. To accomplish this, a coating solution isformed comprising the coating polymer and a solvent. Typical solventsuseful with the cellulosic polymers noted above include acetone, methylacetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methylisobutyl ketone, methyl propyl ketone, ethylene glycol monoethyl ether,ethylene glycol monoethyl acetate, methylene dichloride, ethylenedichloride, propylene dichloride, nitroethane, nitropropane,tetrachloroethane, 1,4-dioxane, tetrahydrofuran, diglyme, and mixturesthereof. A particularly preferred solvent is acetone. The coatingsolution typically will contain 3 to 15 wt % of the polymer, preferably5 to 10 wt %, most preferably 7 to 10 wt %.

[0078] The coating solution may also comprise pore-formers,non-solvents, or plasticizers in any amount so long as the polymerremains substantially soluble at the conditions used to form the coatingand so long as the coating remains water-permeable and has sufficientstrength. Pore-formers and their use in fabricating coatings aredescribed in U.S. Pat. Nos. 5,612,059 and 5,698,220, the pertinentdisclosures of which are incorporated herein. The term “pore former,” asused herein, refers to a material added to the coating solution that haslow or no volatility relative to the solvent such that it remains aspart of the coating following the coating process but that issufficiently water swellable or water soluble such that, in the aqueoususe environment it provides a water-filled or water-swollen channel or“pore” to allow the passage of water thereby enhancing the waterpermeability of the coating. Suitable pore-formers include polyethyleneglycol (PEG), PVP, PEO, HEC, HPMC and other aqueous-soluble cellulosics,water-soluble acrylate or methacrylate esters, polyacrylic acid andvarious copolymers and mixtures of these water soluble or waterswellable polymers. Enteric polymers such as cellulose acetate phthalate(CAP) and HPMCAS are included in this class of polymers. A particularlypreferred pore former is PEG having an average molecular weight from1000 to 8000 daltons. A particularly preferred PEG is one having amolecular weight of 3350 daltons. The inventors have found that toobtain a combination of high water permeability and high strength whenPEG is used as a pore former, the weight ratio of CA:PEG should rangefrom about 6.5:3.5 to about 9:1.

[0079] The addition of a non-solvent to the coating solution results inexceptional performance. By “non-solvent” is meant any material added tothe coating solution that substantially dissolves in the coatingsolution and reduces the solubility of the coating polymer or polymersin the solvent. In general, the function of the non-solvent is to impartporosity to the resulting coating. As described below, porous coatingshave higher water permeability than an equivalent weight of a coating ofthe same composition that is not porous and this porosity, when thepores are gas filled, as is typical when the non-solvent is volatile, isindicated by a reduction in the density of the coating (mass/volume).Although not wishing to be bound by any particular mechanism of poreformation, it is generally believed that addition of a non-solventimparts porosity to the coating during evaporation of solvent by causingthe coating solution to undergo liquid-liquid phase separation prior tosolidification. As described below for the case of using water as thenon-solvent in an acetone solution of cellulose acetate, the suitabilityand amount of a particular candidate material can be evaluated for useas a non-solvent by progressively adding the candidate non-solvent tothe coating solution until it becomes cloudy. If this does not occur atany addition level up to about 50 wt % of the coating solution, itgenerally is not appropriate for use as a non-solvent. When clouding isobserved, termed the “cloud point,” an appropriate level of non-solventfor maximum porosity is the amount just below the cloud point. Whenlower porosities are desired, the amount of non-solvent can be reducedas low as desired. It has been found that suitable coatings can beobtained when the concentration of non-solvent in the coating solutionis greater than about 20% of the non-solvent concentration that resultsin the cloud point.

[0080] Suitable non-solvents are any materials that have appreciablesolubility in the solvent and that lower the coating polymer solubilityin the solvent. The preferred non-solvent depends on the solvent and thecoating polymer chosen. In the case of using a volatile polar coatingsolvent such as acetone or methyl ethyl ketone, suitable non-solventsinclude water, glycerol, ethylene glycol and its low molecular-weightoligomers (e.g., less than about 1,000 daltons), propylene glycol andits low molecular weight oligomers (e.g., less than about 1,000daltons), C₁ to C₄ alcohols such as methanol or ethanol, ethylacetate,acetonitrile and the like.

[0081] In general, to maximize its effect, (e.g., formation of pores),the non-solvent should have similar or less volatility than the coatingsolution solvent such that, during initial evaporation of the solventduring the coating process, sufficient non-solvent remains to causephase separation to occur. In many cases, where a coating solutionsolvent such as acetone is used, water is a suitable non-solvent. Foracetone solutions comprising 7 wt % CA and 3 wt % PEG, the cloud pointat room temperature is at about 23 wt % water. Thus the porosity and inturn the water permeability (which increases with increasing porosity)can be controlled by varying the water concentration up to near thecloud point. For acetone solutions comprising CA and PEG with a totalconcentration of about 10 wt %, it is desired that the coating solutioncontain at least 4 wt % water to obtain a suitable coating. When ahigher porosity, and thus a higher water permeability is desired (toobtain a faster release rate), the coating solution should contain atleast about 15 wt % water.

[0082] In one embodiment of the invention, the coating solution ishomogeneous, in that when the polymer, solvent, and any pore formers ornon-solvents are mixed, the solution comprises a single phase.Typically, a homogenous solution will be clear, and not be cloudy asdiscussed above.

[0083] When using CA 398-10, exemplary coating solution weight ratios ofCA:PEG 3350:water are 7:3:5, 8:2:5, and 9:1:5, with the remainder of thesolution comprising a solvent such as acetone. Thus, for example, in asolution having a weight ratio of CA:PEG 3350:water of 7:3:5, CAcomprises 7 wt % of the solution, PEG 3350 comprises 3 wt % of thesolution, water comprises 5 wt % of the solution, and acetone comprisesthe remaining 85 wt %.

[0084] Preferred coatings are generally porous even in the dry state(prior to delivery to the aqueous use environment). By “porous” is meantthat the coating has a dry-state density less than the density of thenonporous coating material. By “nonporous coating material” is meant acoating material formed by using a coating solution containing nonon-solvent, or the minimum amount of non-solvent required to produce ahomogeneous coating solution. The coating in the dry state has a densitythat is less than 0.9 times, and more preferably less than 0.75 timesthat of the nonporous coating material. The dry-state density of thecoating can be calculated by dividing the coating weight (determinedfrom the weight gain of the tablets before and after coating) by thecoating volume (calculated by multiplying the coating thickness, asdetermined by optical or scanning electron microscopy, by the tabletsurface area). The porous nature of the coating is one of the factorsthat leads to the combination of high water permeability and highstrength of the coating.

[0085] The coatings may also be asymmetric, meaning that there is agradient of density throughout the coating thickness. Generally, theoutside surface of the coating will have a higher density than thecoating nearest the core.

[0086] The coating can optionally include a plasticizer. A plasticizergenerally swells the coating polymer such that the polymer's glasstransition temperature is lowered, its flexibility and toughnessincreased and its permeability altered. When the plasticizer ishydrophilic, such as polyethylene glycol, the water permeability of thecoating is generally increased. When the plasticizer is hydrophobic,such as diethyl phthalate or dibutyl sebacate, the water permeability ofthe coating is generally decreased.

[0087] It should be noted that additives can function in more than oneway when added to the coating solution. For example, PEG can function asa plasticizer at low levels while at higher levels it can form aseparate phase and act as a pore former. In addition, when a non-solventis added, PEG can also facilitate pore formation by partitioning intothe non-solvent-rich phase once liquid-liquid phase separation occurs.

[0088] The weight of the coating around the core depends on thecomposition and porosity of the coating, the surface to volume ratio ofthe dosage form, and the desired drug release rate, but generally shouldbe present in an amount ranging from about 3 to 30 wt %, preferably from8 to 25 wt %, based on the weight of the uncoated core. However, acoating weight of at least about 8 wt % is generally preferred so as toassure sufficient strength for reliable performance, and more preferablya coating greater than about 13 wt %.

[0089] While porous coatings based on CA, PEG, and water yield excellentresults, other pharmaceutically acceptable materials may be used so longas the coating has the requisite combination of high water permeability,high strength, and ease of manufacture. Further, such coatings may bedense, or asymmetric, having one or more dense layers and one or moreporous layers, as described in U.S. Pat. Nos. 5,612,059 and 5,698,220.

[0090] The coating 18 must also contain at least one delivery port 20 incommunication with the interior and exterior of the coating to allow forrelease of the drug-containing composition to the exterior of the dosageform. The delivery port can range in size from about the size of thedrug particles, and thus could be as small as 1 to 100 microns indiameter and may be termed pores, up to about 5000 microns in diameter.The shape of the port may be substantially circular, in the form of aslit, or other convenient shape to ease manufacturing and processing.The port(s) may be formed by post-coating mechanical or thermal means orwith a beam of light (e.g., a laser), a beam of particles, or otherhigh-energy source, or may be formed in situ by rupture of a smallportion of the coating. Such rupture may be controlled by intentionallyincorporating a relatively small weak portion into the coating. Deliveryports may also be formed in situ by erosion of a plug of water-solublematerial or by rupture of a thinner portion of the coating over anindentation in the core. Delivery ports may be formed by coating thecore such that one or more small regions remains uncoated. In addition,the delivery port can be a large number of holes or pores that may beformed during coating, as in the case of asymmetric membrane coatings ofthe type disclosed in U.S. Pat. Nos. 5,612,059 and 5,698,220, thedisclosures of which are incorporated by reference. When the deliverypathways are pores there can be a multitude of such pores that range insize from 1 μm to greater than 100 μm. During operation, one or more ofsuch pores may enlarge under the influence of the hydrostatic pressuregenerated during operation. The number of delivery ports 20 may varyfrom 1 to 10 or more. At least one delivery port should be formed on theside of the coating that is adjacent to the drug-containing composition,so that the drug-containing composition will be extruded out of thedelivery port by the swelling action of the water-swellable composition.It is recognized that some processes for forming delivery ports may alsoform holes or pores in the coating adjacent to the water-swellablecomposition. In aggregate, the total surface area of core exposed bydelivery ports is less than 5%, and more typically less than 1%.

[0091] Other features and embodiments of the invention will becomeapparent from the following examples which are given for illustration ofthe invention rather than for limiting its intended scope.

EXAMPLE 1

[0092] Exemplary dosage forms of the present invention were made with abi-layer core geometry of the type depicted in FIG. 1. The bi-layer coreconsisted of a drug-containing composition and a water-swellablecomposition.

[0093] To form the drug-containing composition the following materialswere blended (see Table A): 35 wt % of the citrate salt of1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenylsulphony]-4-methylpiperazinefor treatment of penile erectile disfunction, also known as sildenafilcitrate (hereinafter referred to as Drug 1) having a solubility of about20 μg/mL at pH 6, 30 wt % xylitol (trade name XYLITAB 200), 29 wt % PEOwith an average molecular weight of 600,000, 5 wt % sodium starchglycolate (trade name EXPLOTAB), and 1 wt % magnesium stearate. Thedrug-containing composition ingredients were first combined without themagnesium stearate and blended for 20 minutes in a TURBULA mixer. Thisblend was pushed through a screen (screen size of 0.065 inch), thenblended again for 20 minutes in the same mixer. Next, magnesium stearatewas added and the drug-containing composition was blended again for 4minutes in the same mixer. To form the water-swellable composition, thefollowing materials were blended: 74.5 wt % EXPLOTAB, 25 wt % of thetableting aid silicified microcrystalline cellulose (trade name PROSOLV90), and 0.5 wt % magnesium stearate. The water-swellable compositionwas formulated in the same manner as the drug-containing composition.

[0094] Tablet cores were formed by placing 400 mg of drug-containingcomposition in a standard {fraction (13/32)} inch die and gentlyleveling with the press. Then, 100 mg water-swellable composition wasplaced in the die on top of the drug-containing composition. The tabletcore was then compressed to a hardness of about 11 Kp. The resultingbi-layer tablet core had a total weight of 500 mg and contained a totalof 28 wt % Drug 1 (140 mg), 24 wt % XYLITAB 200, 23 wt % PEO 600,000,18.9 wt % EXPLOTAB, 5 wt % PROSOLV 90, and 1.1 wt % magnesium stearate.

[0095] Coatings were applied by a Vector LDCS-20 pan coater. The coatingsolution contained CA (CA 398-10 from Eastman Fine Chemical, Kingsport,Tennessee), polyethylene glycol (PEG 3350, Union Carbide), water, andacetone in a weight ratio of 7/3/5/85 (wt %). The flow rate of the inletheated drying air of the pan coater was set at 40 ft³/min with theoutlet temperature set at 25° C. Nitrogen at 20 psi was used to atomizethe coating solution from the spray nozzle, with a nozzle-to-beddistance of 2 inches. The pan rotation was set to 20 rpm. The so-coatedtablets were dried at 50° C. in a convection oven. The final dry coatingweight amounted to 40.5 mg or 8.1 wt % of the tablet core. Five 900 μmdiameter holes were then mechanically drilled in the coating on thedrug-containing composition side of the tablet to provide 5 deliveryports per tablet. Table C summarizes the characteristics of the dosageform.

[0096] To simulate in vivo drug dissolution, tablets were placed in 900mL of a simulated gastric solution (10 mM HCl, 100 mM NaCl, pH 2.0, 261mOsm/kg) for 2 hours, then transferred to 900 mL of a simulatedintestinal environment solution (6 mM KH₂PO₄, 64 mM KCl, 35 mM NaCl, pH7.2, 210 mOsm/kg), both solutions being stirred at 50 rpm. A residualdissolution test was performed as described in the Detailed Descriptionsection. Residual drug was analyzed by HPLC using a Waters Symmetry C₁₈column. The mobile phase consisted of 0.05 M triethanolamine (pH3)/methanol/acetonitrile in a volume ratio of 58/25/17. Drugconcentration was calculated by comparing UV absorbance at 290 nm to theabsorbance of Drug 1 standards. The amount of drug remaining in thetablets was subtracted from the total initial amount of drug in thetablet to obtain the amount released at each time interval. Results areshown in Table 1 and summarized in Table D. TABLE 1 Time Drug (hours)(wt % released) 0 0 2 25 4 46 8 74 14 94 20 98

[0097] The data show that 25 wt % of the drug was released within 2hours, 74 wt % within 8 hours, and 98 wt % of the drug was releasedwithin 20 hours. Thus, the present invention provided a rapid release ofover 70 wt % within 8 hours and very low residual value at 20 hours of arelatively high dose (140 mg) of a low-solubility drug in a relativelylow mass (540 mg) dosage form.

EXAMPLE 2

[0098] This example demonstrates the inventive delivery of a high doseof Drug 1 from bi-layer tablets by increasing the amount of drug in thedrug-containing composition. For the tablets of Example 2, thedrug-containing composition consisted of 56 wt % Drug 1, 20 wt % XYLITAB200, 19 wt % PEO with an average molecular weight of 600,000, 4 wt %EXPLOTAB, and 1 wt % magnesium stearate. The water-swellable compositionconsisted of 74.5 wt % EXPLOTAB, 25 wt % PROSOLV 90, and 0.5 wt %magnesium stearate. These tablets were made as in Example 1, except that500 mg of the drug-containing composition was used to make the tablet.See Table C for further details of the make-up of the tablets. Thedrug-containing composition and water-swellable composition for thisexample were combined in a ratio of 83.3 wt % drug-containingcomposition to 16.7 wt % water-swellable composition. Dissolution testswere performed as described in Example 1. Results are shown in Table 2and summarized in Table D. TABLE 2 Time Drug (hours) (wt % released) 0 02 16 4 34 8 57 14 76 20 86

[0099] The above data show that 16 wt % of the drug was released within2 hours and 86 wt % within 20 hours. Thus, the dosage forms of thepresent invention performed well, even with a high drug loading in thedrug-containing composition.

EXAMPLES 3A-3B

[0100] These examples demonstrate the inventive delivery of variousdrugs from bi-layer tablets. For the tablets of Example 3A, thedrug-containing composition consisted of 35% sertraline HCl (Drug 2)having a solubility of 0.2 mg/mL at pH 7, 30 wt % XYLITAB 200, 28.75 wt% PEO with an average molecular weight of 600,000, 5 wt % EXPLOTAB, and1.25 wt % magnesium stearate. The water-swellable composition consistedof 74.5 wt % EXPLOTAB, 25 wt % PROSOLV 90, and 0.5 wt % magnesiumstearate. These tablets were made as in Example 1. Dissolution testswere performed on these tablets in the same manner as Example 1 exceptthe residual drug was analyzed by HPLC using a Phenomenex Ultracarb 5ODS 20 column. The mobile phase consisted of 35 vol % TEA-acetate buffer(3.48 mL triethanolamine and 2.86 mL glacial acetic acid in 1 L HPLCH₂O) in acetonitrile. Drug concentration was calculated by comparing UVabsorbance at 230 nm to the absorbance of sertraline standards. Theresults are presented in Table 3 and summarized in Table D.

[0101] For the tablets of Example 3B, the drug-containing compositionconsisted of 32.4 wt % of mesylate salt of the drug4-[3-[4-(2-methylimidazol-1-yl)phenylthio]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxamidehemifumarate a 5-lipoxygenase inhibitor for the treatment of chronicinflammatory conditions such as asthma (Drug 3) having a solubility of3.7 mgA/mL at pH 4, 31.2 wt % XYLITAB 200, 29.9 wt % PEO with an averagemolecular weight of 600,000, 5.2 wt % EXPLOTAB, and 1.3 wt % magnesiumstearate (see Table A). The water-swellable composition consisted of74.5 wt % EXPLOTAB, 24.5 wt % PROSOLV 90, and 1 wt % magnesium stearate.These tablets were made as in Example 1. Dissolution tests wereperformed on these tablets in accordance with Example 1 with thefollowing exceptions: residual drug was analyzed by dissolving tabletsin 0.1 N HCl and measuring UV absorbance at 258 nm. Results are shown inTable 3 and summarized in Table D. TABLE 3 Time Drug Example (hours) (%released) 3A 0 0 2 22 4 45 8 79 14 92 20 94 3B 0 0 2 18 4 38 8 68 12 8518 89 24 91

[0102] Examples 3A and 3B show low residual drug after 24 hours withvirtually no lag time. Along with Example 1, these examples show thatdifferent low-solubility drugs can be successfully delivered from dosageforms of this invention.

EXAMPLE 4

[0103] This example demonstrates the inventive delivery of Drug 2 frombi-layer tablets without an ionic swelling agent in the water-swellablecomposition. For the tablets of Example 4, the drug-containingcomposition consisted of 35% Drug 2, 30 wt % XYLITAB 200, 29 wt % PEOwith an average molecular weight of 600,000, 5 wt % EXPLOTAB, and 1 wt %magnesium stearate (see Table A). The water-swellable compositionconsisted of 65 wt % PEO with an average molecular weight of 5,000,000,29.4 wt % NaCl, 5% of the tableting aid hydroxymethylcellulose(METHOCEL), and 0.6 wt % magnesium stearate (see Table B). These tabletswere made as in Example 1, except that 490 mg of the drug-containingcomposition and 245 mg of the water-swellable composition were used tomake the tablet (see Table C). Dissolution tests were performed on thesetablets as described in Example 3A. Results are shown in Table 4 andsummarized in Table D. TABLE 4 Time Drug (hours) (wt % released) 0 0 1 12 15 4 47 8 80 12 90 18 95 24 87

[0104] The data show that 15 wt % of the drug was released within 2hours and 87 wt % was released within 24 hours when there was no ionicswelling agent in the water-swellable composition.

EXAMPLES 5A-5C

[0105] These examples demonstrate that various amounts of ionic swellingagent and tableting aid can be used to form dosage forms with thedesired release profile.

[0106] For the tablets of Examples 5A, 5B, and 5C, the drug-containingcomposition consisted of 35 wt % Drug 1, 30 wt % XYLITAB 200, 29 wt %PEO with an average molecular weight of 600,000, 5 wt % EXPLOTAB, and 1wt % magnesium stearate. The drug-containing composition waswet-granulated using deionized water and dried overnight in a 40° C.oven. For tablets of Example 5A, the water-swellable compositionconsisted of 74.35 wt % EXPLOTAB, 24.85 wt % PROSOLV 90, 0.3 wt % RedLake #40, and 0.3 wt % magnesium stearate. The water-swellablecomposition was formed by wet-granulating the EXPLOTAB and PROSOLV 90using water as solvent, drying this mixture, and then blending with theother ingredients.

[0107] For tablets of Example 5B, the water-swellable compositionconsisted of 49.4 wt % EXPLOTAB, 49.4 wt % PROSOLV 90, 0.2 wt % Red Lake#40, and 1 wt % magnesium stearate. The water-swellable composition waswet-granulated as in Example 5A.

[0108] For tablets of Example 5C, the water-swellable compositionconsisted of 59.35 wt % EXPLOTAB, 39.4 wt % PROSOLV 90, 0.25 wt % RedLake #40, and 1 wt % magnesium stearate. The water-swellable compositionwas wet-granulated as in Example 5A.

[0109] Tablets were formed by placing 400 mg of drug-containingcomposition in a standard {fraction (13/32)} inch die and tampinglightly. Then, 100 mg water-swellable composition was placed in the dieon top of the drug-containing composition. The tablet was thencompressed to a hardness of about 12 Kp. All cores were coated in thesame manner as in Example 1, except the final dry coating weights foreach example were 40.5 mg (8.1 wt %) for 5A, 46.5 mg (9.3 wt %) for 5B,and 43.5 mg (8.7 wt %) for 5C respectively.

[0110] Dissolution tests were performed on these tablets as described inExample 1. Results are shown in Table 5 and summarized in Table D. TABLE5 Time Drug Example (hours) (wt % released) 5A 0 0 EXPLOTAB/ 2 15PROSOLV 90 = 4 43 75/25* 8 69 14 94 20 97 5B 0 0 EXPLOTAB/ 2 15 PROSOLV90 = 4 40 50/50* 8 67 14 89 20 96 5C 0 0 EXPLOTAB/ 2 16 PROSOLV 90 = 440 60/40* 8 69 14 89 20 96

[0111] The data show that the weight ratio of EXPLOTAB to PROSOLV 90 canbe varied from about 75/25 to about 50/50 without any adverse effect onthe desired drug release profile.

EXAMPLE 6

[0112] This example demonstrates that low residual drug values may beobtained with the dosage forms of the invention even with high drugloading. For the tablets of Example 6, the drug-containing compositionand the water-swellable composition were the same as in Example 2, andwere made as in Example 2, except that 200 mg of the water-swellablecomposition was used to make the tablets (71.4% drug-containingcomposition/28.6% water-swellable composition) and the tablets had a77.7 mg (11.1 wt %) coating. Dissolution tests were performed asdescribed in Example 1. Results are shown in Table 6. TABLE 6 Time Drug(hours) (wt % released) 0 0 2 16 4 39 8 65 14 89 20 94

[0113] A comparison of these data with those of Example 2 show that theinitial rate of drug release was the same, releasing 16 wt % of the drugwithin 2 hours. Compared to Example 2, the data also show thatincreasing the amount of water-swellable composition in the core(Example 6) resulted in a higher percentage (94% vs. 86%) of the drugbeing released after 20 hours, thereby leaving a lower amount ofresidual drug.

EXAMPLES 7A-7D

[0114] These examples demonstrate the relationship between the drugrelease profile and the water permeability of the coating. For thetablets of Examples 7A, 7B, 7C, and 7D, the drug-containing compositionconsisted of 35 wt % Drug 1, 30 wt % XYLITAB 200, 29 wt % PEO with anaverage molecular weight of 600,000, 5 wt % EXPLOTAB, and 1 wt %magnesium stearate. The water-swellable composition consisted of 74.35wt % EXPLOTAB, 24.85 wt % PROSOLV 90, 0.3 wt % Red Lake #40, and 0.3 wt% magnesium stearate.

[0115] These tablets were made as in Example 1, except that the tabletshad different amounts of coating (see Table C). For the tablets ofExample 7A, the coating had a final dry weight of 29 mg (5.8 wt %). Forthe tablets of Example 7B, the coating had a final dry weight of 56.5 mg(11.3 wt %). For the tablets of Example 7C, the coating had a final dryweight of 89.5 mg (17.9 wt %). For the tablets of Example 7D, thecoating had a final dry weight of 124.5 mg (24.9 wt %). Generally, thethicker the coating, the lower the expected water permeability.Dissolution tests were performed on these tablets as described inExample 1. Results are shown in Table 7 and are summarized in Table D.TABLE 7 Time Drug Example (hours) (wt % released) 7A 0 0 2 30 4 57 8 8814 98 20 97 7B 0 0 2 19 4 45 8 69 14 94 20 98 7C 0 0 2 8 4 27 8 60 14 8220 94 7D 0 0 2 0 4 17 8 48 14 68 20 88

[0116] Examples 7A-7D show that as the water permeability decreased,i.e., as the coating weight increased, the rate of drug releasedecreased. The data show that as the coating thickness increased, thefraction of drug delivered between 0 and 2 hours decreased, while thefraction of drug delivered from 8 to 20 hours increased.

EXAMPLE 8

[0117] This example demonstrates the delivery of an amorphous dispersionof Drug 2 in a concentration-enhancing polymer from a dosage form of theinvention. Amorphous solid dispersions of Drug 2 in HPMCP were preparedby spray-drying a solution containing 0.65 wt % sertraline free base,0.65 wt % hydroxy propylmethyl cellulose phthalate (HPMCP 55), 49.35 wt% methanol, and 49.35 wt % acetone. The drug was dissolved in themethanol, and the polymer was dissolved in the acetone, before combiningthe solutions. The solution was spray-dried using a two-fluid externalmix spray nozzle at 1.8 bar at a feed rate of 187 to 211 g/min into thestainless steel chamber of a Niro spray-dryer, maintained at atemperature of 230° C. at the inlet and 72° C. at the outlet.

[0118] To form the drug-containing composition, the following materialswere blended: 41.15 wt % sertraline dispersion (1:1 sertraline freebase:HPMCP), 26.75 wt % PEO having an average molecular weight of600,000, 26.75 wt % XYLITAB 200, 4.33 wt % EXPLOTAB, and 1.02 wt %magnesium stearate. The drug-containing composition ingredients werecombined and precompressed, then milled in a co-mill at 1100 rpm with ascreen size having 0.075-inch openings.

[0119] To form the water-swellable composition, the following materialswere blended: 74.66 wt % EXPLOTAB, 24.73 wt % PROSOLV 90, 0.47 wt %magnesium stearate, and 0.14 wt % Red Lake #40. The water-swellablecomposition ingredients were combined without the magnesium stearate,blended 20 minutes in a Turbula mixer, then blended again for 4 minuteswith magnesium stearate. Assays of these tablets confirmed 112 mg ofactive sertraline (mgA).

[0120] Release of the sertraline dispersion from the bi-layer tabletsinto simulated intestinal buffer was measured by HPLC as described inExample 3A. Results are shown in Table 8 and summarized in Table D.TABLE 8 Time Drug (hours) (wt % released) 0 0 1 7 2 17 4 40 8 68 12 8618 91 24 86

[0121] The data demonstrate satisfactory delivery of a sertralinedispersion from dosage forms of this invention.

EXAMPLE 9

[0122] This example illustrates the delivery of another drug dispersionfrom a bi-layer tablet. The drug was in the form of a solid amorphousdispersion comprising 50 wt % of 5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-3-((3R,4S)-dihydroxypyrrolidin-1-yl-)-(2R)-hydroxy-3-oxypropyl] amide (aglycogen phosphorylase inhibitor) (Drug 4) having a water solubility of80 μg/mL and 50% hydroxy proplymethyl cellulose acetate succinate(HPMCAS MF grade). The solid dispersion was prepared in essentially thesame way as Example 8 except as follows: the solution comprised 7.5 wt %Drug 4, 7.5 wt % polymer and 85 wt % 95:5 acetone:H₂O (wt:wt) Thissolution was spray-dried using an external mix 2-fluid atomizer withfeed rates of 460 g/min atomizing gas and 200 g/min solution feed withan inlet temperature of 195° C. and an outlet temperature of 70° C.

[0123] The resulting solid particles had an average diameter ofapproximately 50 μm. The drug-containing composition consisted of 44.4wt % solid dispersion, 26.1 wt % XYLITAB 200, 25.2 wt % PEO with anaverage molecular weight of 600,000, 3.5 wt % EXPLOTAB, and 0.8 wt %magnesium stearate. The water-swellable composition consisted of 74.8 wt% EXPLOTAB, 24.8 wt % PROSOLV 90, and 0.4 wt % magnesium stearate (seeTable B).

[0124] The drug-containing composition ingredients were mechanicallymixed until substantially homogeneous, compressed into a weak tablet,then the resulting tablets were ground to particles less than 16 mesh insize. The water-swellable composition ingredients were then mixed untilsubstantially homogeneous. Tablets were formed by first placing 450 mgof ground drug-containing composition in an f-press in a standard{fraction (15/32)}-inch die and tamping lightly. Then, 150 mg of thewater-swellable composition mixture was placed in the die on top of thedrug-containing composition. The tablet was then compressed to ahardness of 15 Kp.

[0125] The resulting bi-layer tablet core had a total weight of 600 mgand contained 199.8 mg of solid dispersion, 99.9 mg of which was Drug 4.This core was then coated as in Example 1 to obtain a coating weight of8.9%, and five 900 μm holes were drilled on the drug face only of thetablet.

[0126] The dissolution of drug was studied by placing the bi-layertablets in intestinal buffer and stirring at 50 rpm. Tablets weredissolved in 75/25 methanol/water for residual analysis. Drugconcentration over time was determined using a Zorbax SB C18 column,with a mobile phase of 35 vol % acetonitrile in water, and UV absorbancemeasured at 297 nm. The results are shown in Table 9 and are summarizedin Table D.

[0127] The data shows satisfactory release of a dispersion of Drug 4from the bi-layer tablet. TABLE 9 Time Drug (hours) (wt % released) 0 01 1 2 4 4 28 8 63 12 81 18 96 24 97

EXAMPLE 10

[0128] This example illustrates the delivery of5-(2-(4-(3-benzisothiazolyl)-piperazinyl)ethyl-6-chlorooxindole (Drug 5)from a bi-layer tablet. The drug was in the from of a solid dispersioncomprising 10 wt % of Drug 5 having a solubility of 3 μg/mL in modelfasted duodenal solution and 90 wt % HPMCAS, HF grade. The soliddispersion was prepared in essentially the same way as Example 8 exceptas follows: the solution comprised 0.3 wt % Drug 5, 2.7 wt % HPMCAS and97 wt % MeOH. This solution was spray dried at 19 psi and a 140 g/minfeed rate with an inlet temperature of 264° C. and an outlet temperatureof 62° C.

[0129] The drug-containing composition consisted of 45.1 wt % soliddispersion, 25 wt % XYLITAB 200, 25 wt % PEO with an average molecularweight of 600,000, 3.9 wt % EXPLOTAB, and 1% magnesium stearate. Thewater-swellable composition consisted of 74.8 wt % EXPLOTAB, 24.7 wt %PROSOLV 90, and 0.5 wt % magnesium stearate. Tablets were formed byfirst mechanically mixing the above drug-containing compositioningredients until homogeneous, compressing into a tablet of 10-20 Kp,and grinding resulting tablets to particles. The above water-swellablecomposition ingredients were mixed until homogeneous. Bi-layer tabletswere prepared from the drug-containing composition particles andwater-swellable composition, as described in Example 9.

[0130] The resulting bi-layer core had a total weight of 700 mg andcontained 247.8 mg of solid dispersion, 22.84 mg of which was Drug 5.The bi-layer core was then coated as in Example 1 to obtain a coatingweight of 11.3%, and five 2 mM holes were drilled.

[0131] The dissolution of drug was studied by placing the bi-layertablets in intestinal buffer and stirring at 50 rpm. Tablets weredissolved in 75/25 methanol/water (w/w) for analysis for residual drugcontent. Drug concentration was determined using HPLC, with a mobilephase of 60 vol % 0.02 M KH₂PO₄, pH 3.0 in ACN, and diode arraydetection at 254 nm. The results are shown in Table 10 and summarized inTable D. TABLE 10 Time Drug (hours) (wt % released) 0 0 1 5 2 13 4 26 846 12 73 18 76 24 74

[0132] The data shows satisfactory release of a dispersion of Drug 5from the bi-layer tablet.

EXAMPLE 11

[0133] This example demonstrates the inventive delivery of Drug 2 frombi-layer tablets without a swelling agent in the drug-containingcomposition. For the tablets of Example 11, the drug-containingcomposition consisted of 22.8% Drug 2, 71.7 wt % PEO with an averagemolecular weight of 200,000, 5 wt % Methocel, and 0.5 wt % magnesiumstearate. The water-swellable composition consisted of 74.5 wt %EXPLOTAB, 25.0 wt % PROSOLV 90, and 0.5 wt % magnesium stearate. Thesetablets were made as in Example 1, except that 490 mg of thedrug-containing composition and 245 mg of the water-swellablecomposition were used to make the tablet. Dissolution tests wereperformed on these tablets as described in Example 1. Results are shownin Table 11 and summarized in Table D. TABLE 11 Time Drug (hours) (wt %released) 0 0 1 3 2 17 4 49 8 70 12 84 20 88 24 92

[0134] The data show that satisfactory drug delivery was obtained withdosage forms of the invention without a swelling agent in thedrug-containing composition.

EXAMPLE 12

[0135] This example describes the results of tests to determine theswelling volume of swelling agents that may be used in the formulationof the water-swellable composition.

[0136] The following experiment was used to determine the swelling ratioof materials. The materials were first blended and then 500 mg of thematerial was compressed into a tablet using a {fraction (13/32)}-inchdie, the tablet having a strength ranging from 3 to 16 Kp/cm². Thiscompressed material was then placed into a glass cylinder ofapproximately the same inside diameter as the tablet. The height of thetablet was then measured. Using this height and the diameter of thetablet, the volume of the dry material was determined. Next, the glasscylinder was filled with test media of either deionized water, simulatedintestinal buffer, or simulated gastric buffer. The glass cylinder andtest media were all equilibrated at a constant temperature of 37° C. Asthe materials in the tablet absorbed water, the height of the tabletincreased. At each time interval, the height of the tablet was measured,from which the volume of the swollen tablet was determined. The ratio ofthe volume of the tablet after reaching a constant height to that of thevolume of the dry tablet is the swelling ratio of the material. Theresults of these tests are shown in Table 12. TABLE 12 Water-SwellableComposition Swelling Swelling Ratio (v/v) Tableting Agent/ In- SwellingAid/ Tableting Gastric testinal Agent Additive Aid (w/w) Buffer BufferWater PEO 5,000,000 NONE 100/0 2.4 2.4 2.4 PEO 5,000,000 Microcrystal-85/15 2.2 2.1 2.4 line cellulose¹ PEO 5,000,000 Microcrystal- 70/30 2.02.1 2.4 line cellulose PEO 5,000,000 Microcrystal- 50/50 2.0 1.9 1.9line cellulose PEO 5,000,000 NaCl 70/30 2.6 2.6 2.8 PEO 2,000,000Microcrystal- 85/15 2.8 2.8 3.0 line cellulose Polyacrylic Silicified70/30 1.9 1.5 acid² microcrystal- line cellulose³ PolyacrylicMicrocrystal- 50/50 1.8 1.7 acid line cellulose Sodium cros- None 100/07.0 5.4 7.1 carmelose⁴ Sodium cros- Microcrystal- 85/15 7.1 5.9 7.2carmellose line cellulose Sodium cros- Microcrystal- 70/30 5.5 6.3 5.5carmellose line cellulose Sodium cros- Microcrystal- 50/50 4.6 5.3 5.7carmellose line cellulose Sodium starch Microcrystal- 50/50 7.1 7.7 25.2glycolate⁵ line cellulose Sodium starch Microcrystal- 70/30 9.0 9.6 26.8glycolate line cellulose Sodium starch Microcrystal- 85/15 10.9 11.934.7 glycolate line cellulose Sodium starch Silicified 50/50 7.9 8.7glycolate Microcrystal- line cellulose Sodium starch Silicified 75/257.4 9.1 14.4 glycolate Microcrystal- line cellulose Sodium starchSilicified 70/30 10.6 11.2 glycolate Microcrystal- line cellulose Sodiumstarch Hydroxypropyl 98/2 — 17.2 glycolate cellulose⁶ Sodium starchHydroxypropyl 95/5 5.6 8.4 glycolate cellulose Sodium starchHydroxypropyl 90/10 7.2 6.9 glycolate cellulose Sodium starchHydroxypropyl 85/15 — 3.8 3.8 glycolate cellulose Sodium starchHydroxypropyl 70/30 3.7 3.9 3.3 glycolate cellulose Sodium starchHydroxypropyl 50/50 2.4 2.5 2.4 glycolate cellulose Sodium Silicified50/50 2.7 2.9 alginate⁷ microcrystal- line cellulose Hydroxyethyl NONE100/0 2.8 2.8 2.7 cellulose⁸ Hydroxyethyl Microcrystal- 50/50 2.4 2.12.5 cellulose line cellulose

EXAMPLE 13

[0137] Exemplary dosage forms of the present invention were made with abi-layer core geometry of the type depicted in FIG. 1. This exampleillustrates dosage forms of this invention which release drug over ashort duration, utilizing a durable, high permeability coating. Thedrug-containing composition comprised the following materials: 22.8 wt %Drug 2, 71.7 wt % PEO with an average molecular weight of 200,000(Polyox WSR N80), 5.0 wt % METHOCEL K3 LV Prem (a tablet binder), and0.5 wt % of the lubricant, magnesium stearate.

[0138] To form the drug-containing composition, the ingredients (withoutthe magnesium stearate) were blended for 20 minutes in a Turbula mixer.This blend was screened through a 0.065-inch screen, then blended againfor 20 minutes. Next, magnesium stearate was added and the materialswere blended again for 4 minutes. The water-swellable compositioncomprised the following materials: 65.0 wt % PEO with an averagemolecular weight of 5,000,000 (Polyox WSR Coagulant), 29.3 wt % sodiumchloride, 5.1 wt % METHOCEL K3 LV Prem., and 0.6 wt % magnesiumstearate.

[0139] To form the water-swellable composition, the ingredients (withoutthe magnesium stearate) were blended 20 minutes in a Turbula mixer, thenblended again for 4 minutes with magnesium stearate.

[0140] The drug-containing composition and the water-swellablecomposition were tableted together using direct compression. A portionof the drug-containing composition (490 mg) was placed in an f-presswith a standard round concave {fraction (15/32)}-inch die, then gentlyleveled with the upper punch. A 245 mg portion of the water-swellablecomposition was placed on top of this and the tablet compressed. Thecompression distance between the upper and lower punches on the f-presswas adjusted until the hardness of the resulting tablets measured 15 Kp.The resulting bi-layer tablet contained a total of 15.2 wt % SertralineHCl, 47.8 wt % PEO 200,000, 5.0 wt % METHOCEL, 0.5 wt % magnesiumstearate, 21.7 wt % PEO 5,000,000, and 9.8 wt % sodium chloride. Assaysof these tablets confirmed 112 mg of Sertraline HCl, or 100 mg of activeSertraline (mgA).

[0141] The tablets were coated with a high water permeability coating ina Vector LDCS-20 pan coater as described in Example 1. The coatingsolution contained cellulose acetate (CA 398-10), polyethylene glycol(PEG 3350), water, and acetone in a weight ratio of 7/3/5/85. Heateddrying air (40 cfm) was adjusted to maintain the pan coater outlettemperature at 25° C. Nitrogen at 20 psi was used to atomize the coatingsolution from the spray nozzle, with a nozzle-to-bed distance of 2inches. The pan tumbled at 20 rpm. The final dry coating weight amountedto 12.9 wt % of the weight of the tablet core. One 900-μm hole washand-drilled on the face of the tablet. The total weight of the coatedtablet was 830 mg.

[0142] An in vitro residual test was performed as described in Example3A. Results are shown in Table 13 and are summarized in Table D. Thedata show that 19% of the drug was released within 2 hours, and that 98%of the drug was released within 8 hours. Observations of the tabletsduring the release test indicated that the coating was able to withstandthe swelling of the PEO-based core and remained intact for the durationof the test. TABLE 13 Time Drug (hours) (wt % released) 0 0 1 2 2 19 451 8 98 12 99 18 99 24 99

EXAMPLE 14

[0143] This example demonstrates the inventive delivery of Drug 2 from atablet of the present invention, while increasing the percentage of drugin the drug-containing composition to 35 wt %. Tablets for Example 14were made as in Example 13, with ingredients indicated in Tables A, B,and C. Dissolution tests were performed as described in Example 3A.Results are shown in Table 14 and summarized in Table D. TABLE 14 TimeDrug (hours) (wt % released) 0 0 1 7 2 25 4 65 8 97 12 98 18 98 24 98

[0144] The data show that even with a high percentage of drug in thedrug-containing composition, the rate of drug release remained high,showing a release of 25% after 2 hours. Furthermore, 97% of the drug hadbeen released within 8 hours. This example shows that successfuldelivery of drug from dosage forms of this invention can be obtained,even for delivery of large amounts of drug as a percentage of thedrug-containing composition. Such high drug loadings are desirable whendelivery of a high dose of drug is desired while keeping tablet sizeacceptably small.

EXAMPLES 15A-C

[0145] These examples show the effects of the formulation of the coatingmaterial on the water permeability of the coating by measuring the waterflux (40/75), a relative measure of the water permeability of coatingsuseful in comparing coatings. Tablets were made as in Example 13, withthe exceptions noted in Tables A, B, and C. The tablets were made using{fraction (15/32)}-inch tooling, with compression at 13.4 Kp. Eachtablet had a surface area of approximately 4.35 cm².

[0146] Coatings were applied to these tablets as in Example 1. Table15.1 reports the composition of the coating solutions used. Acetone wasused as the solvent in all cases. TABLE 15.1 Coating Solution Coatingweight Formulation (wt %) per Tablet Example CA 398-10 PEG Water mg wt %15A 7 3 5 82 11.2 15B 8 2 5 84 11.4 15C 9 1 5 86 11.7

[0147] To determine water flux (40/75) values, five tablets from eachexample were placed in a weigh boat in an environmental chamber having aconstant temperature of 40° C. and a constant relative humidity of 75%.Periodically, the tablets were removed and weighed. Table 15.2 gives thedata from this experiment. TABLE 15.2 Weight of 5 Tablets (g)Time(Hours) Example 15A Example 15B Example 15C 0 4.0241 4.0383 4.07030.5 4.0491 4.0590 4.0867 1 4.0611 4.0676 4.0948 3 4.0882 4.0901 4.1158 44.0943 4.0966 4.1213 5 4.1025 4.1031 4.1281 6 4.1082 4.1076 4.1338 74.1119 4.1110 4.1370 22 4.1338 4.1303 4.1593 23 4.1374 4.1341 4.1627 244.1406 4.1356 4.1649

[0148] The water flux (40/75) values of the coatings were determined bydividing the initial slope obtained by plotting weight versus time bythe tablet surface area for 5 tablets. Table 15.3 reports the results ofthese calculations (using a linear regression fit of the first threedata points to determine the initial slope. The data show that the waterflux (40/75) values increased as the amount of PEG included in thecoating solution was increased relative to the amount of CA. TABLE 15.3CA/PEG Ratio Water Flux (40/75) Example (by weight) (g/hr · cm²) 15A 7:31.7 × 10⁻³ 15B 8:2 1.4 × 10⁻³ 15C 9:1 1.1 × 10⁻³

EXAMPLES 16A-16U

[0149] These examples measure the “durability” of the coating, arelative measure of the strength of the coatings found to be a usefulmeasure for comparing coatings. For Examples 16A-16G, tablets were madeas in Example 1, with the exceptions noted in Tables A and B. Asindicated in Table C, two different types of coatings and variouscoating weights were used to coat these tablets. The tablets were madeusing {fraction (13/32)}-inch tooling, yielding tablets with a maximumcross-sectional area of 0.84 cm². For Examples 16H-16U, tablets weremade as in Example 14, with the exceptions noted in Tables A and B.These tablets were coated with various coating weights, as indicated inTable C. The tablets were made using {fraction (7/16)}-inch tooling,yielding tablets with a maximum cross-sectional area of 0.97 cm². Table16.1 lists the compositions and coating weights for the tablets ofExample 16. Acetone was used as the solvent in all cases.

[0150] To determine the coating durability, the tablets were placed indeionized water at 37° C. for 16 to 24 hours. The tablets were thenremoved, rinsed in deionized water, and tested for hardness on aSchleuniger tablet hardness tester, Model 6D. Tablets were placed in thetester so that the delivery port was blocked against the tester platewhen force was applied. The durability for each tablet, defined as thetablet hardness (in Kp) divided by the maximum cross-sectional surfacearea (in cm²), was calculated from these tests, and is set forth inTable 16.2. TABLE 16.1 Coating Coating-Solution Weight per Formulation(wt %) Tablet Example CA 398-10 PEG Water Wt % 16A 4 1 2.5 11.7 16B 4 12.5 11.2 16C 8 2 5 6.9 16D 7 3 5 8.1 16E 7 3 5 8.3 16F 7 3 5 12.0 16G 73 5 12.8 16H 7 3 5 12.4 16I 7 3 5 11.1 16J 7 3 5 10.3 16K 7 3 5 7.9 16L7 3 5 11.7 16M 7 3 5 22.8 16N 7 3 5 13.4 16O 7 3 5 18.0 16P 7 3 5 21.616Q 7 3 5 26.8 16R 7 3 5 13.6 16S 7 3 5 18.2 16T 7 3 5 21.4 16U 7 3 525.2

[0151] TABLE 16.2 Durability Example (Kp/cm²) 16A 30.3 16B 20.5 16C 4.316D 10.3 16E 7.6 16F 13.4 16G 12.7 16H 8.5 16I 7.7 16J 7.6 16K 4.0 16L6.0 16M 22.6 16N 13.8 16O 18.7 16P 22.8 16Q 30.6 16R 13.7 16S 17.3 16T23.0 16U 29.8

[0152] These data show that the durabilities of the high permeabilitycoatings of the present invention are high, and that the coatingdurability increases as the amount of coating applied to the tabletincreases. The data also show that for the same amount of coating,coatings made with a high CA/PEG ratio (Examples 16A to 16C) have ahigher durability than those made with a low CA/PEG ratio (Examples 16Dto 16U). These results, combined with the results of Example 15, showthat the coatings of the present invention have high water permeabilityand high strength.

EXAMPLES 17A-17C

[0153] Including solubilizing acids in the drug-containing compositionmay increase the bioavailability of the drug. These examples demonstratethe utility of the present invention to release an organic acid withDrug 2, sertraline. Here, it is desirable that the solubilizing acid isreleased along with the sertraline, so as to increase the solubility ofsertraline in the use environment, which in turn increasesbioavailability.

[0154] In Examples 17A-17C, dosage forms of the present invention weremade wherein the drug-containing composition or the water-swellablecomposition included a solubilizing acid selected from citric acid andfumaric acid. These tablets were made as in Example 3A, with theexceptions noted in Tables A, B, and C. In Example 17A, thedrug-containing composition contained 15 wt % citric acid. In Example17B, the drug-containing composition contained 7 wt % fumaric acid. InExample 17C, both the drug-containing composition and thewater-swellable composition contained 15 wt % citric acid.

[0155] The tablets were dissolution-tested in USP sodium acetate buffer,using the direct test. The results for Examples 17A-C are shown inTables 17.1 and 17.2 and are summarized in Table D. TABLE 17.1 Time DrugExample (hours) (wt % released) 17A 0 0 1 0 2 3 4 23 6 47 8 69 10 88 1291 16 82 20 92 24 92 17B 0 0 1 0 2 9 4 31 6 57 8 79 10 92 12 96 16 96 2096

[0156] TABLE 17.2 Time (wt % released) Example (hours) Drug Citric Acid17C 0 0 0 1 0 0 2 6 9 4 24 28 6 46 47 8 65 62 10 81 76 12 94 84 16 96 8920 96 93

[0157] The results of Examples 17A and 17B show that high rates ofsertraline release (91% and 96% within 12 hours, respectively) may beobtained when including the solubilizing acid in the dosage form.Comparison with dosage forms that do not contain the solubilizing acid(e.g., Example 14) shows that solubilizing acids did not affect therelease profile for the drug.

[0158] The results of Example 17C show that the citric acid was releasedat about the same rate as the sertraline (84% citric acid and 94%sertraline within 12 hours). In addition, citric acid was released atall times when sertraline was released. During the release tests ofExamples 17A-C, the receptor solution in the vicinity of the tablets hada pH of about 3, indicating that including organic acids in the dosageform leads to a locally low pH. This test demonstrates that one mayexpect that the use environment will contain sufficient solubilizingacid in the vicinity of where the drug is released to result in alocally lower pH, in turn causing higher concentration of dissolved drugand, hence, increased bioavailability.

EXAMPLE 18

[0159] This example demonstrates the in vivo release of carprofen (Drug6) from bi-layer tablets. The solubility of Drug 6 is approximately0.015 mg/mL at pH 5.9. For the tablets of Example 18, thedrug-containing composition was composed of 12.6 wt % Drug 6, 52.4 wt %XYLITAB 200, 28.8 wt % PEO with an average molecular weight of 600,000,5.0 wt % Explotab, and 1.2 wt % magnesium stearate; and thewater-swellable composition was composed of 74.4 wt % EXPLOTAB, 24.6 wt% microcrystalline cellulose (AVICEL pH 200), and 1.0 wt % magnesiumstearate. These tablets were made by a direct blend-and-compress methodusing a single-station Manesty f-press with {fraction (13/32)} inchstandard round concave tooling. For these tablets, the drug-containingcomposition made up 400 mg while the water-swellable composition made up100 mg. Tablets contained 50 mg of active drug. The bi-layer core wasthen coated with a coating solution consisting of 7 wt % celluloseacetate, 3 wt % PEG 3350, 5 wt % water, and 85 wt % acetone to obtain acoating weight of 11 wt % (wt/wt core), and four 1 mM slits were made onthe tablet edge. In vivo residual tests were performed in 5 dogs asfollows: one tablet was orally administered to each dog followed by a 50mL gavage. The bowel movements were screened for tablets and therecovery times noted. The residual undelivered drug was determined by aresidual test, and the drug release was calculated by subtracting theresidual amount from the known initial amount of drug present in thetablets. Results are shown in Table 18.1. TABLE 18.1 Time Drug (hours)(wt % released)  9 48, 57, 58 20 84, 92

[0160] These tablets were also tested in vitro using a residualdissolution test. These tests were performed in a USP type 2 dissoetteusing the following conditions: 37° C., 100 rpm, 0.05 M phosphate bufferat pH 7.5. Results are shown in Table 18.2. TABLE 18.2 Time Drug (hours)(wt % released) 0 0 2 12 4 37 8 66 12 78 20 95 24 98

[0161] The data show satisfactory in vivo drug delivery with dosageforms of the invention. Good correlation is observed between in vitroand in vivo data.

EXAMPLE 19

[0162] This example demonstrates the in vivo delivery of Tenidap (Drug7) from bi-layer tablets. The solubility of Drug 7 is 0.2 mg/mL at pH7.4 and 0.002 mg/mL at pH 3.7. For the tablets of Example 19, thedrug-containing composition consisted of 12.5% Drug 7, 37.5 wt % XYLITAB200, 36.15 wt % PEO with an average molecular weight of 600,000, 12.5 wt% EXPLOTAB, and 1.25 wt % magnesium stearate; and the water-swellablecomposition consisted of 74.0 wt % EXPLOTAB, 24.5 wt % microcrystallinecellulose (AVICEL pH 200), 0.5 wt % FD&C Red, and 1.0 wt % magnesiumstearate. These tablets were made using a direct blend-and-compressmanufacturing process on a single-station Manesty f-press. For thesetablets, the drug-containing composition made up 400 mg and thewater-swellable composition made up 100 mg. Tablets contained 50 mgactive Drug 7. The bi-layer core was then coated in a Freund HCT-30 EPcoating pan using a spray solution consisting of 7 wt % celluloseacetate, 3 wt % PEG, 5 wt % water, and 85 wt % acetone to obtain acoating weight of 10% (wt/wt core). Instead of drilling a delivery port,four slits in the coating were made on the edge of each tablet.

[0163] In vivo residual tests were performed in dogs as follows: Each offive dogs were dosed with tablets (so that they could be lateridentified) over a six-hour period (i.e., one tablet every two hours)with oral gavage of 50 mL water. The bowel movement was screened fortablets and the recovery time noted. All tablets were recovered intact,i.e., there were no splits in the coatings. The amount of undelivereddrug was determined by extracting the unreleased drug from the tabletsand the drug released was determined by subtracting the unreleasedamount from the known initial amount of drug present in the tablets.Results are shown in Table 19.1. TABLE 19.1 Time Drug (hours) (wt %released) 4 25.8 (n = 2) 6 43.9 (n = 2) 8 59.7 (n = 1) 20 74.9 (n = 3)21.5 83.3 (n = 1) 22.0 80.2 (n = 2) 23.5 87.7 (n = 1) 24.0 83.6 (n = 2)25.5 87.0 (n = 1)

[0164] In addition to the in vivo test above, residual recovery from apharmacokinetic (PK) study in dogs was performed as follows: dogs weredosed with one tablet each and blood samples withdrawn periodically atselected times. The bowel movements were screened for tablets and therecovery times noted. The residual undelivered drug was determined byextraction and the drug released calculated as described previously. Theresults from the residual PK study agree with the results above; theyare shown in Table 19.2. TABLE 19.2 Time Drug (hours) (wt % released) 857.8 (n = 2) 16-25 83.4 (n = 2)

[0165] These tablets were also tested in vitro using a residualdissolution. The dissolution of tablets with one slit on the tablet faceis shown for comparison. These tests were performed using a USP type 2dissoette under the following conditions: 900 mL pH 7.5 phosphatebuffer, 100 rpm, 37° C. Results are shown in Table 19.3. TABLE 19.3 DrugDrug Time (wt % released) (wt % released) (hours) 4 slits on edge 1 sliton face 0  0  0 2 16  6 4 43 24 8 75 61 12 84 80 20 91 94 24 94 94

[0166] The data show satisfactory in vivo drug delivery with dosageforms of the invention. Good correlation is observed between in vitroand in vivo data.

EXAMPLE 20

[0167] This example shows the utility of including aconcentration-enhancing polymer, a solubilizer, and a fluidizing agentin the drug-containing composition. The drug-containing compositioncomprised the following materials: 20 wt % Drug 2, 15 wt % tartaric acid(a solubilizer), 20 wt % HPMCAS (HPMCAS-LG grade) (aconcentration-enhancing polymer), 29 wt % PEO with an average molecularweight of 600,000 (Polyox WSR-205) (a polymeric entraining agent), 15 wt% xylitol (Xylitab 200) (a fluidizing agent), and 1 wt % of thelubricant, magnesium stearate. To form the drug-containing composition,the ingredients (without the magnesium stearate) were blended for 10minutes in a Turbula mixer. This blend was wet-granulated using a mortarand pestle with a mixture of isopropyl alcohol and water in a volumeratio of 85:15. The wet-granulated material was dried in a 40° C. ovenovernight. The dried granulation was passed through a Fitzpatrick hammermill, model L1A, at 3000 rpm, and screened through a 0.065-inch screen.This material was blended again in the Turbula mixer for 10 minutes.Next, magnesium stearate was added and the materials were blended for 4additional minutes.

[0168] The water-swellable composition comprised the followingmaterials: 64.4 wt % PEO with an average molecular weight of 5 million(Polyox WSR Coagulant), 30 wt % sodium chloride, 5 wt % HPMC (MethocelE5 LV Prem., a tablet binder), 0.1 wt % of a colorant (Red Lake #40),and 0.5 wt % magnesium stearate. To form the water-swellablecomposition, the ingredients (without the colorant or magnesiumstearate) were blended 20 minutes in a twinshell mixer, then milledusing a hammer mill and passed through a 0.098-inch screen. Thismaterial was blended again for 20 minutes in a twinshell mixer. Thecolorant and magnesium stearate were mixed for 1 minute, and then addedto the blend. These ingredients were blended for 4 additional minutes.

[0169] The drug-containing composition and the water-swellablecomposition were tableted together using direct compression to form thecore. A portion of the drug-containing composition (441.5 mg) was placedin an f-press with a standard round concave {fraction (7/16)}-inch die,then gently leveled with the upper punch. A portion of thewater-swellable composition (227.5 mg) was placed on top of the layer ofdrug-containing composition and compressed. The compression distancebetween the upper and lower punches on the f-press was adjusted untilthe hardness of the resulting core measured 11.4 Kp. The resultingbi-layer core weighed 669 mg and contained a total of 13.2 wt %sertraline HCl, 9.9 wt % tartaric acid, 13.2 wt % HPMCAS-LG, 19.1 wt %PEO 600,000, 9.9 wt % xylitol, 0.9 wt % magnesium stearate, 21.9 wt %PEO 5,000,000, 10.2 wt % sodium chloride, 1.7 wt % HPMC, and 0.03 wt %colorant. Assays of these tablets showed 82 mg of Sertraline HCl, or 73mgA of active sertraline.

[0170] The tablets were coated with a high water permeability coating ina Vector LDCS-20 pan coater. The coating solution contained CA 398-10,polyethylene glycol (PEG 3350), water, and acetone in a weight ratio of7/3/5/85. Heated drying air (40 cfm) was adjusted to maintain the pancoater outlet temperature at 25° C. Nitrogen at 20 psi was used toatomize the coating solution from the spray nozzle, with a nozzle-to-beddistance of 2 inches. The pan tumbled at 20 rpm. The final dry coatingweight amounted to 20.4 wt % of the weight of the tablet core. One 2 mMport was laser-drilled on the face of the tablet. The total weight ofthe coated tablet was 805 mg.

[0171] An in vitro residual drug release test was performed. Tabletswere placed in a stirred USP type 2 dissoette flask containing asolution of gastric buffer (10 mM HCl, 100 mM NaCl, pH 2.0, 261 mOsm/kg)for 2 hours, and then transferred to a solution of intestinal buffer (6mM KH₂PO₄, 64 mM KCl, 35 mM NaCl, pH 7.2, 210 mOsm/kg). In both flasks,the dosage form was placed in a wire support to keep the tablet off ofthe bottom of the flask so that all surfaces were exposed to thesolution, and the solutions were stirred using paddles rotating at 50revolutions per minute. At spaced-apart time intervals, a single tabletwas removed and placed in recovery solution (50/50 wt/wt ethanol/water,pH 3) to dissolve the drug remaining in the tablet. Residual drug wasanalyzed by HPLC using a Phenomenex Ultracarb 5 ODS 20 column. Themobile phase consisted of 35 vol % TEA-acetate buffer (3.48 mLtriethanolamine and 2.86 mL glacial acetic acid in 1 L HPLC-grade H₂O)in acetonitrile. Drug concentration was calculated by comparing UVabsorbance at 230 nm to the absorbance of known drug standards. Theamount remaining in the tablets was subtracted from the initial amountof drug in the tablets (73 mgA) to obtain the amount released at eachtime interval. Results are shown in Table 20 and are summarized in TableD. TABLE 20 Time Drug (hours) (wt % A released) 0 0 1 3 2 4 4 32 8 74 1278 16 86 20 89

[0172] The data show that 4 wt %A of the drug was released within 2hours, and that 74 wt %A of the drug was released within 8 hours. After20 hours, 89% of the drug contained in the tablet had been released.Observations of the tablets during the release test indicated that thecoating remained intact for the duration of the test.

[0173] For comparison, identical tablets were prepared but without thefluidizing agent xylitol. During dissolution tests of these tablets, itwas observed that the coating on one out of every 4 tablets split. Thus,including a fluidizing agent in the formulation (as in Example 20)reduced the pressure at which the drug-containing composition wasdelivered through the delivery ports. TABLE A Summary of Drug-ContainingComposition for All Examples [Mg [Drug] [Explotab] [Xylitab Stearate]Other Conc. Example Drug wt % [PEO] Type [PEO] wt % wt % 200] wt % wt %Ingredients wt % Processing Method  1 1 35 600K 29 5.0 30.0 1.0 DryBlended  2 1 56 600K 19 4.0 20.0 1.0 Dry Blended 3A 2 35.0 600K 28.755.0 30.0 1.25 Dry Blended 3B 3 32.4 600K 29.9 5.2 31.2 1.3 Dry Blended 42 35.0 600K 29.0 5.0 30.0 1.0 Dry Blended 5A 1 35.0 600K 29 5 30 1.0 Wetgranulated 5B 1 35.0 600K 29 5 30 1.0 Wet granulated 5C 1 35.0 600K 29 530 1.0 Wet granulated  6 1 56.0 600K 19.0 4.0 20.0 1.0 Dry Blended 7A 135 600K 29.0 5.0 30.0 1.0 Dry Blended 7B 1 35 600K 29.0 5.0 30.0 1.0 DryBlended 7C 1 35 600K 29.0 5.0 30.0 1.0 Dry Blended 7D 1 35 600K 29.0 5.030.0 1.0 Dry Blended  8 2 20.57 600K 26.75 4.33 26.75 1.0 HPMCP 20.57Precompressed, comilled  9 4 22.2 600K 25.2 3.5 26.1 0.8 HPMCAS-MF 22.2Dry Blended 10 5 4.16 600K 25 3.9 25 1.0 HPMCAS-HF 40.94 Dry Blended 112 22.8 200K 71.7 0 0 0.5 Methocel 5.0 Dry Blended K3LV 13 2 22.8 200K71.7 0 0 0.5 Methocel 5.0 Dry Blended K3LV 14 2 35 200K 59.6 0 0 0.5Methocel 5.0 Dry Blended K3LV 15A 2 22.8 200K 71.7 0 0 0.5 Methocel 5.0Dry Blended K3LV 15B 2 22.8 200K 71.7 0 0 0.5 Methocel 5.0 Dry BlendedK3LV 15C 2 22.8 200K 71.7 0 0 0.5 Methocel 5.0 Dry Blended K3LV 16A—16G1 35 600K 29 5.0 30.0 1.0 Dry Blended 16H—16U 2 35 200K 59.6 0 0 0.5Methocel 5.0 Dry Blended K3LV 17A 2 30 200K 49.5 0 0 1.5 Klucel EF 4.5Dry Blended Citric acid 15.0 17B 2 37.8 200K 48.8 0 0 1.0 Klucel EF 4.9Dry Blended Fumaric acid 7.0 17C 2 29.9 200K 49.2 0 0 1.5 Klucel EF 4.5Dry Blended Citric acid 14.9 18 6 12.6 600K 28.8 5.0 52.4 1.2 DryBlended 19 7 12.5 600K 36.15 12.5 37.5 1.25 Dry Blended 20 2 20 600K 290 15 1.0 Tartaric acid 15 Blended, wet-granulated w/ HPMCAS 20 IPA/H2O(85/15),dried, milled, blended

[0174] TABLE B Summary of Water-Swellable Composition for All Examples[Prosolv 90] [Mg Stearate] Other Example [Explolab] wt % wt % wt %Ingredients Conc. wt % Processing Method 1  74.5 25 0.5 Dry Blended 2 74.5 25 0.5 Dry Blended 3A 74.5 25 0.5 Dry Blended 3B 74.5 24.5 1.0 DryBlended 4  0 0 0.6 Methocel K3LV 5.0 Dry Blended PEO 5 million 65.0 NaCl29.4 5A 74.35 24.85 0.3 Red Lake #40 0.3 Wet granulated 5B 49.4 49.4 1.0Red Lake #40 0.25 Wet granulated 5C 59.35 39.4 1.0 Red Lake #40 0.25 Wetgranulated 6  74.3 25.2 0.5 Dry Blended 7A 74.35 24.85 0.3 Red Lake #400.3 Dry Blended 7B 74.35 24.85 0.3 Red Lake #40 0.3 Dry Blended 7C 74.3524.85 0.3 Red Lake #40 0.3 Dry Blended 7D 74.35 24.85 0.3 Red Lake #400.3 Dry Blended 8  74.66 24.73 0.47 Red Lake #40 0.14 Dry Blended 9 74.8 24.8 0.4 Dry Blended 10 74.8 24.7 0.5 Dry Blended 11 74.5 25.0 0.5Dry Blended 13 0 0 0.6 Methocel K3LV 5.1 Dry Blended PEO 5 million 65.0NaCl 29.3 14 0 0 0.6 Methocel K3LV 5.1 Dry Blended PEO 5 million 65.0NaCl 29.3  15A 0 0 0.6 Methocel K3LV 5.1 Dry Blended PEO 5 million 65.0NaCl 29.3  15B 0 0 0.6 Methocel K3LV 5.1 Dry Blended PEO 5 million 65.0NaCl 29.3  15C 0 0 0.6 Methocel K3LV 5.1 Dry Blended PEO 5 million 65.0NaCl 29.3 16A-16G 74.5 25 0.5 Dry Blended 16H-16U 0 0 0.6 Methocel K3LV5.1 Dry Blended PEO 5 million 65.0 NaCl 29.3  17A 0 0 0.6 Methocel K3LV5.9 Dry Blended PEO 5 million 64.3 NaCl 29.2  17B 0 0 0.5 Methocel K3LV5.1 Dry Blended PEO 5 million 64.4 NaCl 29.9 Red Lake #40 0.1  17C 0 00.6 Methocel K3LV 5.9 Dry Blended PEO 5 million 64.3 NaCl 14.6 Citricacid 14.6 18 74.4 0 1.0 Avicel 24.6 Dry Blended 19 74.0 0 1.0 Avicel24.5 Dry Blended Red Lake #40 0.5 20 0 0 0.5 Methocel K3LV 5.0 DryBlended PEO 5 million 64.4 NaCl 30.0 Red Lake #40 0.1

[0175] TABLE C Summary of Details of Tablet Formulations for AllExamples Core Ratio of Drug to Coating Amount Number Weight SwellerLayer [PEG] [H2O] wt % of uncoated of Port size Example (mg) Drug LayerSweller Layer (w/w) [CA] wt % wt % wt % tablet Ports (μrr)  1 500 400100 4.0 7 3 5 8.1 5 900  2 600 500 100 5.0 7 3 5 10.6 5 900 3A 500 400100 4.0 7 3 5 9.6 5 900 3B 500 400 100 4.0 7 3 5 10.2 5 900  4 735 490245 2.0 7 3 5 13.0 1 900 5A 500 400 100 4.0 7 3 5 8.1 5 900 5B 500 400100 4.0 7 3 5 9.3 5 900 5C 500 400 100 4.0 7 3 5 8.7 5 900  6 700 500200 2.5 7 3 5 11.1 5 900 7A 500 400 100 4.0 7 3 5 5.8 5 900 7B 500 400100 4.0 7 3 5 11.3 5 900 7C 500 400 100 4.0 7 3 5 17.9 5 900 7D 500 400100 4.0 7 3 5 24.9 5 900  8 700 550 150 3.7 7 3 5 9.7 5 2000  9 600 450150 3.0 7 3 5 8.9 5 900 10 700 550 150 3.7 7 3 5 11.3 5 900 11 735 490245 2.0 7 3 5 12.6 1 900 13 735 490 245 2.0 7 3 5 12.9 1 900 14 735 490245 2.0 7 3 5 13.0 1 900 15A 735 490 245 2.0 7 3 5 11.2 1 900 15B 735490 245 2.0 8 2 5 11.4 1 900 15C 735 490 245 2.0 9 1 5 11.7 1 900 16A500 400 100 4.0 4 1 2.5 11.7 5 900 16B 500 400 100 4.0 4 1 2.5 11.2 5900 16C 500 400 100 4.0 8 2 5 6.9 5 900 16D 500 400 100 4.0 7 3 5 8.1 5900 16E 500 400 100 4.0 7 3 5 8.3 5 900 16F 500 400 100 4.0 7 3 5 12.0 5900 16G 500 400 100 4.0 7 3 5 12.8 5 900 16H 735 490 245 2.0 7 3 5 12.41 900 16I 735 490 245 2.0 7 3 5 11.1 1 900 16J 735 490 245 2.0 7 3 510.3 1 900 16K 735 490 245 2.0 7 3 5 7.9 1 900 16L 735 490 245 2.0 7 3 511.7 1 900 16M 735 490 245 2.0 7 3 5 22.8 1 900 16N 735 490 245 2.0 7 35 13.4 1 900 16O 735 490 245 2.0 7 3 5 18.0 1 900 16P 735 490 245 2.0 73 5 21.6 1 900 16Q 735 490 245 2.0 7 3 5 26.8 1 900 16R 735 490 245 2.07 3 5 13.6 1 900 16S 735 490 245 2.0 7 3 5 18.2 1 900 16T 735 490 2452.0 7 3 5 21.4 1 900 16U 735 490 245 2.0 7 3 5 25.2 1 900 17A 887 591296 2.0 7 3 5 21.9 1 700 17B 700 469 231 2.0 7 3 5 20.0 1 700 17C 887591 296 2.0 7 3 5 21.9 1 700 18 500 400 100 4.0 7 3 5 11 4 1000 (slits)19 500 400 100 4.0 7 3 5 10 4 1000 (slits) 20 669 441.5 227.5 1.9 7 3 520.4 1 2000 

[0176] TABLE D Summary of Release Rates in wt % for All Examples*Example 2-hr release (%) 8-hr release (%) 12-hr release (%) 16-hrrelease (%) 20-hr release 24-hr release (%) 1  25 74 87 95 98 2  16 5770 78 86 3A 22 79 88 93 94 3B 18 68 85 88 91 4  15 80 90 93 87 5A 15 6986 95 97 5B 15 67 82 91 96 5C 16 69 82 91 96 6  16 65 81 91 94 7A 30 8895 98 (14-hr) 97 7B 19 69 86 95 98 7C 8 60 75 85 94 7D 0 48 61 75 88 8 17 68 86 89 86 9  4 63 81 91 97 10 13 46 73 75 74 11 17 70 84 86 92 1319 98 99 99 99 14 25 97 98 98 98  17A 3 69 91 82 92  17B 9 79 96 96 9617C (drug) 6 65 94 96 96 17C (citric acid) 9 62 84 89 93 18 12 66 78 8798 19 (in vivo) 12.9 59.7 64.8 69.8 83.6 20 4 74 78 86 89

[0177] The terms and expressions which have been employed in theforegoing specification are used therein as terms of description and notof limitation, and there is no intention, in the use of such terms andexpressions, of excluding equivalents of the features shown anddescribed or portions thereof, it being recognized that the scope of theinvention is defined and limited only by the claims which follow.

1. A controlled release drug dosage form comprising a core and a coatingaround said core wherein: (a) said core comprises a drug-containingcomposition and a water-swellable composition, each occupying separateregions within said core; (b) said drug-containing composition comprisesa drug, a swelling agent, and a drug-entraining agent; (c) said coatingis water-permeable, water-insoluble, and has at least one delivery porttherethrough; (d) said swelling agent has a swelling ratio of at least3.5; and (e) said drug-entraining agent comprises at least 15 wt % ofsaid drug-containing composition.
 2. A controlled release drug dosageform comprising a core and a coating around said core wherein: (a) saidcore comprises a drug-containing composition and a water-swellablecomposition, each occupying separate regions within said core; (b) saiddrug-containing composition comprises a drug and a drug-entrainingagent; (c) said water-swellable composition comprises a swelling agentand a tableting aid; (d) said coating is water-permeable,water-insoluble, and has at least one delivery port therethrough; (e)the mass ratio of said drug-containing composition to saidwater-swellable composition has a value of at least 1.5; (f) saidwater-swellable composition has a swelling ratio of at least 3.5; and(g) said core has a strength following tableting of at least 3 Kp/cm².3. A controlled release drug dosage form comprising a core and a coatingaround said core wherein: (a) said core comprises a drug-containingcomposition and a water-swellable composition, each occupying separateregions within said core; (b) said drug-containing composition comprisesa drug and a drug-entraining agent; and (c) said coating iswater-permeable, water-insoluble, has at least one delivery porttherethrough, has a water flux (40/75) of at least 1.0×10⁻³ gm/cm²·hr,and a durability of at least 1 Kp/cm².
 4. A controlled release dosageform comprising a core and a coating around said core wherein: (a) saidcore comprises a drug-containing composition and a water-swellablecomposition, each occupying separate regions within said core; (b) saiddrug-containing composition comprises a drug and a drug-entrainingagent; and (c) said coating is water-permeable, water-insoluble, has atleast one delivery port therethrough, is porous and is formed from asubstantially homogeneous solution comprising a solvent, a cellulosicpolymer, and a non-solvent.
 5. A controlled release drug dosage formcomprising a core and a coating around said core wherein: (a) said corecomprises a drug-containing composition and a water-swellablecomposition, each occupying separate regions within said core; (b) saiddrug-containing composition comprises a drug, a drug-entraining agent,and a fluidizing agent, said fluidizing agent having a solubility of atleast 30 mg/mL and comprising at least 10 wt % of said drug-containingcomposition; and (c) said coating is water-permeable, water-insoluble,and has at least one delivery port therethrough, wherein at least about70 wt % of said low-solubility drug is released to a use environmentwithin about 12 hours after introduction to said use environment.
 6. Acontrolled release dosage form comprising a core and a coating aroundsaid core wherein: (a) said core comprises a drug-containing compositionand a water-swellable composition, each occupying separate regionswithin said core; (b) said drug-containing composition comprises a drug,a solubilizer, and a drug-entraining agent; and (c) said coating iswater-permeable, water-insoluble, and has at least one delivery porttherethrough.
 7. The dosage form of any one of claims 1-6 wherein saiddrug-entraining agent is selected from the group consisting of polyols,oligomers of polyethers, mixtures of polyfunctional organic acids,cationic materials, polyethylene oxide, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, carboxyethylcellulose, gelatin, and xanthan gum.
 8. Thedosage form of claim 7 wherein said drug-entraining agent is selectedfrom the group consisting of polyethylene oxide, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, carboxyethylcellulose, gelatin, and xanthan gum.
 9. Thedosage form of claim 8 wherein said drug-entraining agent ispolyethylene oxide.
 10. The dosage form of claim 1 wherein said swellingagent is an ionic swelling agent.
 11. The dosage form of claim 10wherein said ionic swelling agent is selected from the group consistingof sodium croscarmellose and sodium starch glycolate.
 12. The dosageform of any one of claims 2-6 wherein said drug-containing compositionfurther comprises a swelling agent.
 13. The dosage form of claim 12wherein said swelling agent of said drug-containing composition is anionic swelling agent.
 14. The dosage form of claim 13 wherein saidswelling agent of said drug-containing composition is selected from thegroup consisting of sodium croscarmellose and sodium starch glycolate.15. The dosage form of claim 14 wherein said swelling agent of saiddrug-containing composition comprises sodium croscarmellose.
 16. Thedosage form of claim 14 wherein said swelling agent of saiddrug-containing composition comprises sodium starch glycolate.
 17. Thedosage form of any one of claims 1-5 wherein said core includes asolubilizer.
 18. The dosage form of claim 17 wherein saiddrug-containing composition further includes a concentration-enhancingpolymer.
 19. The dosage form of claim 17 wherein said solubilizer is anorganic acid, and said drug has enhanced solubility in the presence ofsaid organic acid.
 20. The dosage form of any one of claims 1-5 whereinsaid drug-containing composition further comprises a solubilizer. 21.The dosage form of claim 20 wherein said solubilizer is an organic acid,and said drug has enhanced solubility in the presence of said organicacid.
 22. The dosage form of any one of claims 1-6 wherein saidwater-swellable composition includes a solubilizer.
 23. The dosage formof claim 22 wherein said solubilizer is an organic acid, and saidlow-solubility drug has enhanced solubility in the presence of saidorganic acid.
 24. The dosage form of claim 23 wherein saiddrug-containing composition further comprises a concentration-enhancingpolymer.
 25. The dosage form of any one of claims 1-4 and 6 wherein saiddrug-containing composition further comprises a fluidizing agent. 26.The dosage form of claim 25 wherein said fluidizing agent is selectedfrom the group consisting of an organic acid, a salt, a sugar, an aminoacid, a polyol, and a low-molecular weight oligomer of a water-solublepolymer.
 27. The dosage form of claim 26 wherein said fluidizing agentis selected from the group consisting of a sugar and an organic acid.28. The dosage form of claim 27 wherein said sugar is selected from thegroup consisting of glucose, sucrose, xylitol, fructose, mannitol,sorbitol, lactose, and maltitol.
 29. The dosage form of claim 28 whereinsaid sugar is xylitol.
 30. The dosage form of claim 27 wherein saidorganic acid is selected from the group consisting of citric acid,lactic acid, ascorbic acid, tartaric acid, malic acid, fumaric acid, andsuccinic acid.
 31. The dosage form of claim 30 wherein said organic acidis citric acid.
 32. The dosage form of claim 31 wherein said organicacid is tartaric acid.
 33. The dosage form of claim 5 wherein saidfluidizing agent is selected from the group consisting of an organicacid, a salt, a sugar, an amino acid, a polyol, and a low-molecularweight oligomer of a water-soluble polymer.
 34. The dosage form of claim33 wherein said fluidizing agent is chosen from the group consisting ofa sugar and an organic acid.
 35. The dosage form of claim 34 whereinsaid sugar is selected from the group consisting of glucose, sucrose,xylitol, fructose, mannitol, sorbitol, lactose and maltitol.
 36. Thedosage form of claim 34 wherein said sugar is xylitol.
 37. The dosageform of claim 34 wherein said organic acid is selected from the groupconsisting of citric acid, lactic acid, ascorbic acid, tartaric acid,malic acid, fumaric acid, and succinic acid.
 38. The dosage form ofclaim 37 wherein said organic acid is citric acid.
 39. The dosage formof claim 37 wherein said organic acid is tartaric acid.
 40. The dosageform of any one of claim 1, 3, 4, 5 or 6 wherein said water-swellablecomposition comprises a swelling agent.
 41. The dosage form of claim 40wherein said swelling agent in said water-swellable composition isselected from the group consisting of polyethylene oxide, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,methyl cellulose, carboxyethyl cellulose, gelatin, and xanthan gum. 42.The dosage form of claim 40 wherein said swelling agent of saidwater-swellable composition is an ionic swelling agent.
 43. The dosageform of claim 42 wherein said swelling agent of said water-swellablecomposition is selected from the group consisting of sodium starchglycolate and sodium croscarmellose.
 44. The dosage form of claim 2wherein said swelling agent of said water-swellable composition is anionic swelling agent.
 45. The dosage form of claim 2 wherein saidswelling agent of said water-swellable composition is selected from thegroup consisting of sodium starch glycolate and sodium croscarmellose.46. The dosage form of any one of claim 1, 3, 4, 5 or 6 wherein saidwater-swellable composition has a swelling ratio of at least 3.5. 47.The dosage form of claim 46 wherein said swelling ratio of saidwater-swellable composition is at least
 5. 48. The dosage form of claim46 wherein said swelling ratio of said water-swellable composition is atleast
 7. 49. The dosage form of claim 2 wherein said swelling ratio ofsaid water-swellable composition is at least
 5. 50. The dosage form ofclaim 2 wherein said swelling ratio of said water-swellable compositionis at least
 7. 51. The dosage form of claim 2 wherein said tableting aidis selected from the group comprising microcrystalline cellulose,hydroxypropylcellulose, methyl cellulose, and hydroxpropylmethylcellulose.
 52. The dosage form of any of claim 40 wherein saidwater-swellable composition further includes a tableting aid.
 53. Thedosage form of claim 52 wherein said tableting aid is selected from thegroup comprising microcrystalline cellulose, hydroxypropylcellulose,methyl cellulose, and hydroxpropylmethyl cellulose.
 54. The dosage formof any of claim 1, 3, 4, 5 or 6 wherein the mass ratio of saiddrug-containing composition to said water-swellable composition is atleast 1.5
 55. The dosage form of claim 54 wherein the mass ratio of saiddrug-containing composition to said water-swellable composition is atleast 3.5.
 56. The dosage form of claim 2 wherein the mass ratio of saiddrug-containing composition to said water-swellable composition is atleast 3.5.
 57. The dosage form of any one of claims 1-6 wherein saidlow-solubility drug is selected from the group consisting of sildenafiland pharmaceutically acceptable salts of sildenafil.
 58. The dosage formof any one of claims 1-6 wherein said low-solubility drug is selectedfrom the group consisting of sertraline and pharmaceutically acceptablesalts of sertraline.
 59. The dosage form of any one of claims 1-6wherein said low-solubility drug is the mesylate salt of the drug4-[3-[4-(2-methylimidazol-1-yl) phenylthio]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide hemifumarate.
 60. Thedosage form of any one of claims 1-6 wherein said low-solubility drug is5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-3-((3R,4S)-dihydroxypyrrolidin-1-yl-)-(2R)-hydroxy-3-oxypropyl] amide.
 61. Thedosage form of any one of claims 1-6 wherein said low-solubility drug is5-(2-(4-(3-benzisothiazolyl)-piperazinyl)ethyl-6-chlorooxindole.
 62. Thedosage form of any one of claims 1-6 wherein said low-solubility drug iscarprofen.
 63. The dosage form of any one of claims 1-6 wherein saiddrug has a maximum solubility of 20 mg/mL in aqueous solution that has apH between 1 and
 8. 64. The dosage form of any one of claims 1-6 whereinsaid drug is a low-solubility drug.
 65. The dosage form of any one ofclaims 1-6 wherein said drug is substantially water insoluble.
 66. Thedosage form of any one of claims 1-6 wherein said drug is sparinglywater soluble.
 67. The dosage form of any of claim 1, 2, 4, 5 or 6wherein said coating has a water flux (40/75) of at least 1.0×10⁻³gm/cm²-hr.
 68. The dosage form of claim 67 wherein said coating has adurability of at least 1 Kp/cm².
 69. The dosage form of any one ofclaims 1-6 wherein said coating comprises a hydrophilic cellulosicpolymer.
 70. The dosage form of claim 69 wherein said cellulosic polymeris selected from cellulose esters, cellulose ethers and celluloseesters/ethers.
 71. The dosage form of claim 69 wherein said hydrophiliccellulosic polymer is selected from the group consisting of celluloseacetate, and mixtures of cellulose acetate and a second polymer.
 72. Thedosage form of claim 71 wherein said hydrophilic cellulosic polymer hasa degree of substitution equivalent to 25 to 42 wt % acetyl groups. 73.The dosage form of claim 71 wherein said cellulose acetate has anaverage molecular weight of at least 45,000.
 74. The dosage form of anyone of claims 1-6 wherein said coating is formed from a solution havinga weight ratio of cellulose acetate to polyethylene glycol of from 9:1to 6.5:3.5.
 75. The dosage form of any one of claims 1-6 wherein saidcoating is formed from a solution having a water concentration ofgreater than 4 wt %.
 76. The dosage form of claim 74 wherein saidsolution has a water concentration of greater than 4 wt %.
 77. Thedosage form of any one of claims 1-6 wherein said coating is formed froma solution having a water concentration of greater than 15 wt %.
 78. Thedosage form of claim 74 wherein said solution has a water concentrationgreater than 15 wt %.
 79. The dosage form of any one of claims 1-6wherein said coating includes at least a pore former.
 80. The dosageform of claim 79 wherein said pore former is selected from the groupconsisting of polyethylene glycol, polyvinyl pyrrolidone, polyethyleneoxide, hydroxyethyl cellulose, hydroxypropyl methyl cellulose,water-soluble acrylate esters, water-soluble methacrylate esters, andpolyacrylic acids.
 81. The dosage form of claim 79 wherein said poreformer is polyethylene glycol.
 82. The dosage form of claim 4 whereinsaid non-solvent is selected from the group consisting of water,glycerol, C₁ to C₄ alcohols, ethylene glycerol and its oligomers andpropylene glycol and its oligomers.
 83. The dosage form of claim 4wherein said solvent is acetone.
 84. The dosage form of claim 4 whereinsaid cellulosic polymer is cellulose acetate.
 85. The dosage form ofclaim 4 wherein said solvent is acetone, said pore former ispolyethylene glycol and said non-solvent is water.
 86. The dosage formany one of claims 82 and 84 wherein said solution has a waterconcentration of greater than 4 wt %.
 87. The dosage form of claim 86wherein said solution has a water concentration greater than 15 wt %.88. The dosage form of any one of claims 1-3, and 5-6 wherein saidcoating is porous and is formed from a homogeneous solution comprising asolvent, a hydrophilic cellulosic polymer, and a non-solvent.
 89. Thedosage form of claim 88 wherein said solution further comprises a poreformer.
 90. The dosage form of claim 89 wherein said pore former ispolyethylene glycol.
 91. The dosage form of claim 88 wherein saidnon-solvent is water.
 92. The dosage form of claim 88 wherein saidsolvent is acetone.
 93. The dosage form of claim 88 wherein saidhydrophilic cellulosic polymer is cellulose acetate.
 94. The dosage formof claim 93 wherein said solvent is acetone, said pore former is PEG,and said non-solvent is water.
 95. The dosage form of any one of claim1, 2, 3, 5 or 6 wherein said coating is porous with a dry-state densityof less than 0.9 times that of the same coating material in nonporousform.
 96. The dosage form of claim 95 wherein said coating has adry-state density of less than 0.75 times that of the same coatingmaterial in nonporous form.
 97. The dosage form of claim 95 wherein saidcoating comprises a polymeric asymmetric membrane comprising a thick,porous region and a dense thin region.
 98. The dosage form of claim 4wherein said coating is porous with a dry-state density of less than 0.9times that of the same nonporous coating material in nonporous form. 99.The dosage form of claim 98 wherein said coating has a dry-state densityof less than 0.75 times that of the same coating material in nonporousform.
 100. The dosage form of claim 98 wherein said coating comprises apolymeric asymmetric membrane comprising a thick, porous region and adense thin region.
 101. The dosage form of any one of claims 1-6 whereinsaid coating has a mass of from 3 to 30 wt % of said core.
 102. Thedosage form of claim 99 wherein said coating has a mass of from 8 to 25wt % of said core.
 103. The dosage form of any one of claims 1-6wherein, following introduction of said dosage form to a useenvironment, no more than 50 wt % of said drug is released to said useenvironment within 2 hours and at least 60 wt % to said use environmentis released within 12 hours.
 104. The dosage form of any one of claim 1,2, 3, 4 or 6 wherein, following introduction of said dosage form to ause environment, at least 60 wt % of said drug is released to said useenvironment within 12 hours.
 105. The dosage form of any one of claim 1,2, 3, 4 or 6 wherein, following introduction of said dosage form to ause environment, at least about 70 wt % of said drug is released to saiduse environment within about 12 hours.
 106. The dosage form of any oneof claims 1-6 wherein, following introduction of said dosage form to ause environment, at least 80 wt % of said drug is released to said useenvironment within 24 hours.
 107. The dosage form of any one of claims1-6 wherein, following introduction of said dosage form to a useenvironment, at least 90 wt % of said drug is released to said useenvironment within 24 hours.
 108. The dosage form of any one of claims1-6 wherein, following introduction of said dosage form to a useenvironment, at least 95 wt % of said drug is released to said useenvironment within 24 hours.
 109. The dosage form of claim 4 whereinsaid substantially homogeneous solution further comprises a pore former.110. The dosage form of claim 4 wherein said non-solvent is present insaid substantially homogeneous solution in an amount greater than 20% ofits concentration at the cloud point.
 111. The dosage form of claim 4wherein said coating has a dry-state density of less than 90% of thedensity of a nonporous coating of the same composition.
 112. The dosageform of claim 4 wherein said at least one delivery port is formed, atleast in part, in the use environment.
 113. A controlled release dosageform comprising a core and a coating around said core wherein: (a) saidcore comprises a drug-containing composition and a water-swellablecomposition, each occupying separate regions within said core; (b) saiddrug-containing composition comprises a low-solubility drug and adrug-entraining agent; and (c) said coating is water-permeable,water-insoluble, and has at least one delivery port therethrough; and(d) wherein said low-solubility drug is in the form of an amorphousdispersion.
 114. The dosage form of claim 113 wherein said amorphousdispersion is a solid dispersion of low-solubility drug in aconcentration-enhancing polymer.
 115. The dosage form of claim 114wherein said concentration-enhancing polymer is selected from the groupconsisting of (a) ionizable cellulosic polymers; (b) non-ionizablecellulosic polymers; and (c) vinyl polymers and copolymers havingsubstituents selected from the group consisting of hydroxyl,alkylacyloxy, and cyclicamido.
 116. The dosage form of claim 115 whereinsaid concentration-enhancing polymer is a cellulosic polymer selectedfrom the group consisting of cellulosic esters, cellulosic ethers, andcellulosic esters/ethers.
 117. The dosage form of claim 115 wherein saidconcentration-enhancing polymer is selected from the group consisting ofpolyvinyl pyrrolidone, polyvinyl alcohol, copolymers of polyvinylpyrrolidone and polyvinyl acetate and aqueous-soluble cellulosicpolymers.
 118. The dosage form of any of claims 1 to 6 wherein saidlow-solubility drug is in the form of an amorphous dispersion.
 119. Thedosage form of claim 118 wherein said amorphous dispersion is a soliddispersion of low-solubility drug in a concentration-enhancing polymer.120. The dosage form of claim 119 wherein said concentration-enhancingpolymer is selected from the group consisting of (a) ionizablecellulosic polymers; (b) non-ionizable cellulosic polymers; and (c)vinyl polymers and copolymers having substituents selected from thegroup consisting of hydroxyl, alkylacyloxy, and cyclicamido.
 121. Thedosage form of claim 120 wherein said concentration-enhancing polymer isa cellulosic polymer selected from the group consisting of cellulosicesters, cellulosic ethers, and cellulosic esters/ethers.
 122. The dosageform of claim 120 wherein said concentration-enhancing polymer isselected from the group consisting of polyvinyl pyrrolidone, polyvinylalcohol, copolymers of polyvinyl pyrrolidone and polyvinyl acetate andaqueous-soluble cellulosic polymers.
 123. A method for treating adisorder, comprising administering to a mammal in need of suchtreatment, including a human patient, a therapeutically effective amountof drug in a dosage form as defined in claim
 1. 124. A method fortreating a disorder, comprising administering to a mammal in need ofsuch treatment, including a human patient, a therapeutically effectiveamount of drug in a dosage form as defined in claim
 2. 125. A method fortreating a disorder, comprising administering to a mammal in need ofsuch treatment, including a human patient, a therapeutically effectiveamount of drug in a dosage form as defined in claim
 3. 126. A method fortreating a disorder, comprising administering to a mammal in need ofsuch treatment, including a human patient, a therapeutically effectiveamount of drug in a dosage form as defined in claim
 4. 127. A method fortreating a disorder, comprising administering to a mammal in need ofsuch treatment, including a human patient, a therapeutically effectiveamount of drug in a dosage form as defined in claim
 5. 128. A method fortreating a disorder, comprising administering to a mammal in need ofsuch treatment, including a human patient, a therapeutically effectiveamount of drug in a dosage form as defined in claim
 6. 129. A method fortreating a disorder, comprising administering to a mammal in need ofsuch treatment, including a human patient, a therapeutically effectiveamount of drug in a dosage form as defined in claim
 113. 130. The dosageform of any one of claims 1-6 wherein said drug-containing compositionfurther includes a concentration-enhancing polymer.
 131. The dosage formof claim 130 wherein said concentration-enhancing polymer is selectedfrom the group consisting of (a) ionizable cellulosic polymers; (b)non-ionizable cellulosic polymers; and (c) vinyl polymers and copolymershaving substituents selected from the group consisting of hydroxyl,alkylacyloxy, and cyclicamido.